Peroxisome proliferator activated receptor modulators

ABSTRACT

The present invention is directed to compounds represented by the following structural formula, and pharmaceutically acceptable salts thereof, Formula I: wherein: (a) R5 is selected from the group consisting of (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkenyl, substituted aryl(C 0 -C 4 )alkyl, substituted aryloxy(C 0 -C 4 )alkyl, substituted arylthio(C 0 -C 4 )alkyl, unsubstituted aryl(C 0 -C 4 )alkyl, unsubstituted aryloxy(C 0 -C 4 )alkyl, and unsubstituted arylthio(C 0 -C 4 )alkyl; (b) T1 is C or N; (c) Q is selected from the group consisting of O, a single bond, O(CH 2 ) q  and C; (d) q is 1 or 2; (e) W is selected from the group consisting of O, S, (CH 2 ) r N(R20)(CH 2 ) k , NHSO 2 , C(O)N(R20)(CH 2 ) r , (CH 2 ) r N(R20)C(O), and SO 2 ; (f) X is C m H 2m ; (g) m is 0, 1 or 2; (h) A is an functional group selected from the group consisting of carboxyl, C1-C3 alkylnitrile, carboxamide, and (CH 2 ) n  COOR19; and (i) R19 is selected from the group consisting of hydrogen, optionally substituted C1-C4alkyl and optionally substituted arylmethyl

This Application claims the benefit of U.S. Provisional Application Ser.No. 60/359,807, filed Feb. 25, 2002 and PCT Application Ser. No.PCT/US03/02680, filed Feb. 13, 2003.

BACKGROUND OF THE INVENTION

Peroxisome Proliferator Activated Receptors (PPARs) are members of thenuclear hormone receptor super family, which are ligand-activatedtranscription factors regulating gene expression. Various subtypes ofPPARs have been discovered. These include PPARα, NUC1, PPARγ and PPARδ.

The PPARα receptor subtypes are reported to be activated by medium andlong-chain fatty acids. They are involved in stimulating beta-oxidationof fatty acids and with the activity of fibrates which reportedlyproduce a substantial reduction in plasma triglycerides and moderatereduction in low density lipoprotein (LDL) cholesterol.

PPARα, PPARγ and PPARδ receptors have been implicated in diabetesmellitus, cardiovascular disease, obesity, Syndrome X andgastrointestinal disease, such as, inflammatory bowel disease. SyndromeX is the combination of symptoms which include hyperinsulemia combinedwith hypertension, elevated body weight, elevated triglycerides andelevated LDL.

Current PPAR agonist treatment for Syndrome X relates to the use ofthiazolidinediones (TZDs) or other insulin sensitivity enhancers (ISEs).TZDs are a class of PPAR gamma agonists which have been shown toincrease the sensitivity of insulin sensitive cells. Increasing insulinsensitivity rather than the amount of insulin in the blood reduces thelikelihood of hypoglycemic coma. However, TZDs and ISEs typically havelittle effect in preventing the cardiovascular part of Syndrome X inthat their administration usually dose not result in the lowering oftriglycerides and LDL-cholesterol while raising HDL-cholesterol.Furthermore, side effects commonly associated with treatment with TZDsinclude significant weight gain, and, for troglitazone, liver toxicity.Therefore, a need exists for new pharmaceutical agents which affect,treat or prevent cardiovascular disease, particularly that associatedwith Syndrome X, while preventing or minimizing weight gain, and morepreferably while improving insulin sensitivity. It may be especiallydesirable when the active pharmaceutical agent selectively modulates aPPAR receptor subtype to provide an especially desirable pharmacologicalprofile.

SUMMARY OF THE INVENTION

The present invention is directed to compounds represented by thefollowing structural Formula I:

and pharmaceutically acceptable salts thereof, wherein:

-   -   (a) R3 is selected from the group consisting of hydrogen and        C1-C3 alkoxy;    -   (b) R4 is selected from the group consisting of hydrogen and        C₁-C₄ alkyl;    -   (c) R5 is selected from the group consisting of (C₁-C₆) alkyl,        (C₁-C₆) alkenyl, aryl(C₀-C₄)alkyl, aryloxy(C₀-C₄)alkyl,        arylthio(C₀-C₄)alkyl, wherein said aryl(C₀-C₄)alkyl,        aryloxy(C₀-C₄)alkyl, and arylthio(C₀-C₄)alkyl are each        independently optionally substituted with from one to three        substituents each independently selected from R5′;    -   (d) R5′ are each independently selected from the group        consisting of halo, —(O)—(C₁-C₅)alkylCOOH, C₁-C₅alkylCOOH, C₁-C₅        alkyl, and CF₃;    -   (e) R6 is selected from the group consisting of trifluoromethyl,        trifluoromethoxy, hydroxy(C₁-C₃)alkyl, (C₁-C₄)alkyl, —C(O)        (C₁-C₄)alkyl, —O—(C₁-C₂)alkyl-CO₂H, aryloxy, arylthio,        [1,3,2]dioxaborolanyl, pyridinyl, pyrimidinyl, pyrazinyl and        aryl(C₀-C₄)alkyl, wherein said pyridinyl, pyrimidinyl,        pyrazinyl, aryl(C₀-C₄)alkyl, aryloxy, and arylthio are each        optionally substituted with from one to three substituents        independently selected from R6′, with the proviso that when T₁        is C and R6 is aryl(C₀-C₄)alkyl, then said aryl(C₀-C₄)alkyl is        substituted with at least one substituent selected from R6′;    -   (f) R6′ is independently selected from the group consisting of        CF₃, C₁-C₄ alkyl, halo, hydroxy(C₀-C₃)alkyl, C₁-C₃ alkoxy, and        —C(O)CH₃;    -   (g) R7 and R8 are each independently selected from the group        consisting of hydrogen, (C₁-C₆) alkyl, and trifluoromethyl;    -   (h) R9 and R10 are each independently selected from the group        consisting of hydrogen, (C₁-C₄) alkyl, (C₁-C₃) alkenyl, halo,        and (C₁-C₄) alkoxy;    -   (i) T₁ is N or C;    -   (j) Q is selected from the group consisting of O, a single bond,        O(CH₂)_(q) and C;    -   (k) q is 1 or 2;    -   (l) W is selected from the group consisting of O, S,        (CH₂)_(r)N(R20) (CH₂)_(k), NHSO₂, C(O)N(R20) (CH₂)_(r),        (CH₂)_(r)N(R20)C(O), and SO₂;    -   (m) r is selected from the group consisting of 0, 1, and 2;    -   (n) k is selected from the group consisting of 0, 1, and 2;    -   (o) R20 is selected from the group consisting of H, C₁-C₃ alkyl,        C(O)OR23, and

-   -   (p) R23 is selected from the group consisting of H and C₁-C₃        alkyl;    -   (q) X is C_(m)H_(2m);    -   (r) m is selected from the group consisting of 0, 1 and 2;    -   (s) Y and Z are each independently selected from the group        consisting of N, S, and O, with the proviso that at least one of        Y and Z is selected from the group consisting of S and O;    -   (t) A is selected from the group consisting of carboxyl, C₁-C₃        alkylnitrile, carboxamide, and (CH₂)_(n)COOR19;    -   (u) n is 0, 1, 2 or 3; and    -   (v) R19 is selected from the group consisting of hydrogen,        C1-C4alkyl and arylmethyl, wherein said alky and arylmethyl are        each optionally substituted with from one to three substituents        each independently selected from R19′;    -   (w) R19′ are each independently selected from the group        consisting of halo, —(O)—(C₁-C₅)alkylCOOH, C₁-C₅ alkyl, and CF₃;    -   with the proviso that when R3 and R4 are each hydrogen, and at        least one selected from the group consisting of R6, R7 and R8 is        CF₃, then R5 is selected from the group consisting of (C₃-C₆)        alkyl, (C₁-C₆) alkenyl, substituted aryl(C₀-C₄)alkyl,        substituted aryloxy(C₀-C₄)alkyl, substituted        arylthio(C₀-C₄)alkyl, unsubstituted aryl(C₀-C₄)alkyl,        unsubstituted aryloxy(C₀-C₄)alkyl, and unsubstituted        arylthio(C₀-C₄)alkyl.        Another embodiment of the present invention is a compound of        Formula I′:

and pharmaceutically acceptable salts thereof, wherein:

-   -   (a) R3 is selected from the group consisting of hydrogen and        C1-C3 alkoxy;    -   (b) R4 is selected from the group consisting of hydrogen and        C₁-C₄ alkyl;    -   (c) R5 is selected from the group consisting of (C₁-C₆) alkyl,        (C₁-C₆) alkenyl, substituted aryl(C₀-C₄)alkyl, substituted        aryloxy(C₀-C₄)alkyl, substituted arylthio(C₀-C₄)alkyl,        unsubstituted aryl(C₀-C₄)alkyl, unsubstituted        aryloxy(C₀-C₄)alkyl, and unsubstituted arylthio(C₀-C₄)alkyl;    -   (d) R6 is selected from the group consisting of trifluoromethyl,        hydroxy(C₁-C₃)alkyl, (C₁-C₄)alkyl, —C(O) (C₁-C₄)alkyl,        —O—(C₁-C₂)alkyl-CO₂H, and substituted aryl(C₀-C₄)alkyl;    -   (e) R7 and R8 are each independently selected from the group        consisting of hydrogen, (C₁-C₆) alkyl, and trifluoromethyl;    -   (f) R9 and R10 are each independently selected from the group        consisting of hydrogen, (C₁-C₄) alkyl, (C₁-C₃) alkenyl, halo,        and (C₁-C₄) alkoxy;    -   (g) Q is selected from the group consisting of O and C;    -   (h) W is selected from the group consisting of O, S, and SO₂;    -   (i) X is C_(m)H_(2m);    -   (j) m is 1 or 2;    -   (k) Y and Z are each independently selected from the group        consisting of N, S, and O;    -   (l) A is an functional group selected from the group consisting        of carboxyl, C₁-C₃alkylnitrile, carboxamide, and        (CH₂)_(n)COOR19;    -   (m) n is 0, 1, 2 or 3; and    -   (n) R19 is selected from the group consisting of hydrogen,        optionally substituted C1-C4alkyl and optionally substituted        arylmethyl;    -   with the proviso that when R3 and R4 are each hydrogen, and at        least one selected from the group consisting of R6, R7 and R8 is        CF₃, then R5 is selected from the group consisting of (C₃-C₆)        alkyl, (C₁-C₆) alkenyl, substituted aryl(C₀-C₄)alkyl,        substituted aryloxy(C₀-C₄)alkyl, substituted        arylthio(C₀-C₄)alkyl, unsubstituted aryl(C₀-C₄)alkyl,        unsubstituted aryloxy(C₀-C₄)alkyl, and unsubstituted        arylthio(C₀-C₄)alkyl.

In another feature of this invention, a compound claimed herein isradiolabeled.

In one embodiment, the present invention also relates to pharmaceuticalcompositions which comprising at least one compound of the presentinvention, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.

In another embodiment, the present invention relates to a method ofselectively modulating a PPAR alpha receptor by contacting the receptorwith at least one compound represented by Structural Formula I, andpharmaceutically acceptable salts thereof.

In another embodiment, the present invention relates to a method ofmodulating one or more of the PPAR alpha, gamma, and/or delta receptors.

In another embodiment, the present invention contemplates the use of oneor more compounds of Formula I for selectively modulating a deltareceptor.

In a further embodiment, the present invention relates to a method ofmaking a compound represented by Structural Formula I.

The compounds of the present invention can be effective in treating andpreventing Syndrome X, Type II diabetes, hyperglycemia, hyperlipidemia,obesity, coagaulopathy, hypertension, atherosclerosis, and otherdisorders related to Syndrome X and cardiovascular diseases. Inaddition, the compounds can be associated with fewer clinical sideeffects than compounds currently used to treat these conditions.Further, compounds of this invention can be useful for loweringfibrinogen, increasing HDL levels, treating renal disease, controllingdesirable weight, treating demyelinating diseases, treating certainviral infections, and treating liver disease.

DETAILED DESCRIPTION OF THE INVENTION

The terms used to describe the instant invention have the followingmeanings herein.

As used herein, when m is 0, then X is absent.

As used herein, when Q is a bond or a single bond, then Q is absent.

As used herein, alkyl groups include straight chained or branchedhydrocarbons, which are completely saturated.

Cycloalkyl groups, as used herein, include cyclic hydrocarbons, whichare partially or completely saturated.

As used herein, aryl groups include carbocyclic aromatic ring systems(e.g. phenyl), fused polycyclic aromatic ring systems (e.g. naphthyl andanthracenyl) and aromatic ring systems fused to carbocyclic non-aromaticring systems (e.g., 1,2,3,4-tetrahydronaphthyl and benzodioxyl). Oneespecially preferred aryl is phenyl.

When R19 is substituted, it is preferred that there are from 1-3substitutions on said R19 group. When R5 or R6 are substituted, it isespecially preferred that there are 1 or 2 independent substituents onsaid R5 or R6 group.

When a compound represented by Structural Formula I has more than onechiral substituent it may exist in diastereoisomeric forms. Thediastereoisomeric pairs may be separated by methods known to thoseskilled in the art, for example chromatography or crystallization andthe individual enantiomers within each pair may be separated usingmethods familiar to the skilled artisan. The present invention includeseach diastereoisomer of compounds of Structural Formula I and mixturesthereof.

Certain compounds of Structural Formula I may exist in different stableconformational forms which may be separable. Torsional asymmetry due torestricted rotation about an asymmetric single bond, for example becauseof steric hindrance or ring strain, may permit separation of differentconformers. The present invention includes each conformational isomer ofcompounds of Structural Formula I and mixtures thereof.

Certain compounds of Structural Formula I may exist in zwitterionic formand the present invention includes each zwitterionic form of compoundsof Structural Formula I and mixtures thereof.

As used herein, the phrase “selectively modulate” means a compound whoseEC50 for the stated PPAR receptor is at least ten fold lower than itsEC50 for the other PPAR receptor subtypes.

“Pharmaceutically-acceptable salt” refers to salts of the compounds ofthe Structural Formula I which are substantially non-toxic to mammals.Typical pharmaceutically-acceptable salts include those salts preparedby reaction of the compounds of the present invention with a mineral ororganic acid or an organic or inorganic base. Such salts are known asbase addition salts, respectively. It should be recognized that theparticular counterion forming a part of any salt of this invention isnot of a critical nature, so long as the salt as a whole ispharmaceutically-acceptable and as long as the counterion does notcontribute undesired qualities to the salt as a whole.

By virtue of its acidic moiety, a compound of Structural Formula I formssalts with pharmaceutically acceptable bases.

Compounds of Structural Formula I, which are substituted with a basicgroup, may exist as salts with pharmaceutically acceptable acids. Thepresent invention includes such salts. These salts may be prepared bymethods known to those skilled in the art.

The term, active ingredient means the compounds generically described byStructural Formula I as well as the salts of such compounds.

The term pharmaceutically acceptable means that the carrier, diluent,excipients and salt must be compatible with the other ingredients of thecomposition, and not deleterious to the recipient thereof.Pharmaceutical compositions of the present invention are prepared byprocedures known in the art using well known and readily availableingredients.

Preventing refers to reducing the likelihood that the recipient willincur or develop any of the pathological conditions described herein.The term preventing is particularly applicable to a patient that issusceptible to the particular patholical condition.

Treating refers to mediating a disease or condition and preventing, ormitigating, its further progression or ameliorating the symptomsassociated with the disease or condition.

“Pharmaceutically-effective amount” means that amount of a compound, orof its salt thereof, that will elicit the biological or medical responseof a tissue, system, or mammal. Such an amount can be administeredprophylactically to a patient thought to be susceptible to developmentof a disease or condition. Such amount when administeredprophylactically to a patient can also be effective to prevent or lessenthe severity of the mediated condition. Such an amount is intended toinclude an amount sufficient to modulate a selected PPAR receptor or toprevent or mediate a disease or condition. Conditions prevented ortreated by modulation of one or more PPAR receptors include diabetesmellitus, cardiovascular disease, Syndrome X, obesity andgastrointestinal disease. Generally, the effective amount of a Compoundof Formula I will be between 0.02 through 5000 mg per day. Preferably 1through 1,500 mg per day. The desired dose may be presented in a singledose or as divisded doses administered at appropriate intervals.

A “mammal” is an individual animal that is a member of the taxonomicclass Mammalia. The class Mammalia includes humans, monkeys,chimpanzees, gorillas, cattle, swine, horses, sheep, dogs, cats, mice,and rats.

Administration to a human is most preferred. The compounds andcompositions of the present invention are useful for the treatmentand/or prophylaxis of cardiovascular disease, for raising serum HDLcholesterol levels, for lowering serum triglyceride levels and for lowerserum LDL cholesterol levels. Elevated triglyceride and LDL levels, andlow HDL levels, are risk factors for the development of heart disease,stroke, and circulatory system disorders and diseases.

The compounds and compositions of the present invention are also usefulfor treating and/or preventing obesity.

Further, these compounds and compositions are useful for the treatmentand/or prophylaxis of non-insulin dependent diabetes mellitus (NIDDM)with reduced or no body weight gains by the patients. Furthermore, thecompounds and compositions of the present invention are useful to treator prevent acute or transient disorders in insulin sensitivity, such assometimes occur following surgery, trauma, myocardial infarction, andthe like. The physician of ordinary skill will know how to identifyhumans who will benefit from administration of the compounds andcompositions of the present invention.

The present invention further provides a method for the treatment and/orprophylaxis of hyperglycemia in a human or non-human mammal whichcomprises administering an effective, non-toxic amount of a compound ofthe general formula (I), or a tautomeric form thereof and/or apharmaceutically acceptable salt thereof to a hyperglycemic human ornon-human mammal in need thereof.

The invention also relates to the use of a compound of Formula I asdescribed above, for the manufacture of a medicament for use in treatinga PPAR receptor mediated condition.

A therapeutically effective amount of a compound of Structural Formula Ican be used for the preparation of a medicament useful for treatingSyndrome X, diabetes, treating obesity, lowering tryglyceride levels,lowering serum LDL levels, raising the plasma level of high densitylipoprotein, and for treating, preventing or reducing the risk ofdeveloping atherosclerosis, and for preventing or reducing the risk ofhaving a first or subsequent atherosclerotic disease event in mammals,particularly in humans. In general, a therapeutically effective amountof a compound of the present invention typically reduces serumtriglyceride levels of a patient by about 20% or more, and increasesserum HDL levels in a patient. Preferably, HDL levels will be increasedby about 30% or more. In adition, a therapeutically effective amount ofa compound, used to prevent or treat NIDDM, typically reduces serumglucose levels, or more specifically HbA1c, of a patient by about 0.7%or more.

Advantageously, compositions containing the compound of StructuralFormula I or the salts thereof may be provided in dosage unit form,preferably each dosage unit containing from about 1 to about 500 mg. Itwill, of course, be readily understood that the amount of thecompound(s) of Structural Formula I actually to be administered will bedetermined by a physician, in the light of all the relevantcircumstances.

When used herein Syndrome X includes pre-diabetic insulin resistancesyndrome and the resulting complications thereof, insulin resistance,non-insulin dependent diabetes, dyslipidemia, hyperglycemia obesity,coagulopathy, hypertension and other complications associated withdiabetes. The methods and treatments mentioned herein include the aboveand encompass the treatment and/or prophylaxis of any one of or anycombination of the following: pre-diabetic insulin resistance syndrome,the resulting complications thereof, insulin resistance, Type II ornon-insulin dependent diabetes, dyslipidemia, hyperglycemia, autoimmuneconditions, obesity and the complications associated with diabetesincluding cardiovascular disease, especially atherosclerosis.

The compositions are formulated and administered in the same generalmanner as detailed herein. The compounds of the instant invention may beused effectively alone or in combination with one or more additionalactive agents depending on the desired target therapy. Combinationtherapy includes administration of a single pharmaceutical dosagecomposition containing a compound of Structural Formula I and one ormore additional active agents, as well as administration of a compoundof Structural Formula I and each active agent in its own separatepharmaceutical dosage formulation. For example, a compound of StructuralFormula I or thereof and an insulin secretogogue such as biguanides,thiazolidinediones, sulfonylureas, insulin, or α-glucosidose inhibitorscan be administered to the patient together in a single oral dosagecomposition such as a tablet or capsule, or each agent administered inseparate oral dosage formulations. Where separate dosage formulationsare used, a compound of Structural Formula I and one or more additionalactive agents can be administered at essentially the same time, i.e.,concurrently, or at separately staggered times, i.e., sequentially;combination therapy is understood to include all these regimens.

An example of combination treatment or prevention of atherosclerosis maybe wherein a compound of Structural Formula I or salts thereof isadministered in combination with one or more of the following activeagents: antihyperlipidemic agents; plasma HDL-raising agents;antihypercholesterolemic agents, fibrates, vitamins, aspirin, and thelike. As noted above, the compounds of Structural Formula I can beadministered in combination with more than one additional active agent.

Another example of combination therapy can be seen in treating diabetesand related disorders wherein the compounds of Structural Formula I,salts thereof can be effectively used in combination with, for example,sulfonylureas, biguanides, thiazolidinediones, α-glucosidase inhibitors,other insulin secretogogues, insulin as well as the active agentsdiscussed above for treating atherosclerosis.

The compounds of the present invention, and the pharmaceuticallyacceptable salts, have valuable pharmacological properties and can beused in pharmaceutical compositions containing a therapeuticallyeffective amount of a compound of the present invention, orpharmaceutically acceptable salts thereof, in combination with one ormore pharmaceutically acceptable excipients. Excipients are inertsubstances such as, without limitation carriers, diluents, fillers,flavoring agents, sweeteners, lubricants, solubilizers, suspendingagents, wetting agents, binders, disintegrating agents, encapsulatingmaterial and other conventional adjuvants. Proper formulation isdependent upon the route of administration chosen. Pharmaceuticalcompositions typically contain from about 1 to about 99 weight percentof the active ingredient.

Preferably, the pharmaceutical formulation is in unit dosage form. A“unit dosage form” is a physically discrete unit containing a unit dose,suitable for administration in human subjects or other mammals. Forexample, a unit dosage form can be a capsule or tablet, or a number ofcapsules or tablets. A “unit dose” is a predetermined quantity of theactive compound of the present invention, calculated to produce thedesired therapeutic effect, in association with one or morepharmaceutically-acceptable excipients. The quantity of activeingredient in a unit dose may be varied or adjusted from about 0.1 toabout 1000 milligrams or more according to the particular treatmentinvolved.

The dosage regimen utilizing the compounds of the present invention isselected by one of ordinary skill in the medical or veterinary arts, inview of a variety of factors, including, without limitation, thespecies, age, weight, sex, and medical condition of the recipient, theseverity of the condition to be treated, the route of administration,the level of metabolic and excretory function of the recipient, thedosage form employed, the particular compound and salt thereof employed,and the like.

Preferably, the compounds of the present invention are administered in asingle daily dose, or the total daily dose may be administered individed doses, two, three, or more times per day. Where delivery is viatransdermal forms, of course, administration is continuous.

Suitable routes of administration of pharmaceutical compositions of thepresent invention include, for example, oral, eyedrop, rectal,transmucosal, topical, or intestinal administration; parenteral delivery(bolus or infusion), including intramuscular, subcutaneous,intramedullary injections, as well as intrathecal, directintraventricular, intravenous, intraperitoneal, intranasal, orintraocular injections. The compounds of the invention can also beadministered in a targeted drug delivery system, such as, for example,in a liposome coated with endothelial cell-specific antibody.

Solid form formulations include powders, tablets and capsules. A solidcarrier can be one or more substances that may also act as flavoringagents, lubricants, solubilisers, suspending agents, binders, tabletdisintegrating agents and encapsulating material.

Sterile liquid formulations include suspensions, emulsions, syrups, andelixirs. The active ingredient can be dissolved or suspended in apharmaceutically acceptable carrier, such as sterile water, sterileorganic solvent, or a mixture of both sterile water and sterile organicsolvent.

Pharmaceutical compositions of the present invention can be manufacturedin a manner that is itself known, e.g., by means of conventional mixing,dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or lyophilizing processes.

The following pharmaceutical formulations 1 and 2 are illustrative onlyand are not intended to limit the scope of the invention in any way.“Active Ingredient”, refers to a compound according to StructuralFormula I or salts thereof.

Formulation 1

Hard gelatin capsules are prepared using the following ingredients:

Quantity (mg/capsule) Active Ingredient 250 Starch, dried 200 Magnesiumstearate 10 Total 460 mg

Formulation 2

A tablet is prepared using the ingredients below:

Quantity (mg/tablet) Active Ingredient 250 Cellulose, microcrystalline400 Silicon dioxide, fumed 10 Stearic acid 5 Total 665 mgThe components are blended and compressed to form tablets each weighing665 mg.

In yet another embodiment of the compounds of the present invention, thecompound is radiolabelled, such as with carbon-14, or tritiated. Saidradiolabelled or tritiated compounds are useful as reference standardsfor in vitro assays to identify new selective PPAR receptor agonists.

The compounds of the present invention can be useful as pharmaceuticalagents and as research tools. Certain compounds and conditions withinthe scope of this invention are preferred. The following conditions,invention embodiments, and compound characteristics listed in tabularform may be independently combined to produce a variety of preferredcompounds and process conditions. The following list of embodiments ofthis invention is not intended to limit the scope of this invention inany way.

Some prefered characteristics of compounds of formula I are:

-   -   a) R3 and R4 are each hydrogen;    -   b) R3 and R4 are each methyl;    -   c) R3 is hydrogen;    -   d) R4 is methyl;    -   e) R3 is alkoxy;    -   f) A is carboxyl;    -   g) R9 is methyl;    -   h) R10 is hydrogen;    -   i) Q is O;    -   j) Q is C;    -   k) W is O;    -   l) X is CH₂;    -   m) Z is N;    -   n) Z is O;    -   o) Y is O;    -   p) Y is S;    -   q) R5 is C₂-C₆ alkyl;    -   r) R5 is substituted aryloxyalkyl;    -   s) R5 is C₁-C₄alkyl;    -   t) R5 is arylalkyl;    -   u) R6 is CF₃;    -   v) R6 is pyrazinyl;    -   w) R6 is pyradinyl;    -   x) R6 is pyrimidinyl;    -   y) R7 is CF₃;    -   z) R7 is CH₃;    -   aa) R8 is hydrogen;    -   bb) T₁ is C;    -   cc) T₁ is N;    -   dd) W is attached to the phenyl ring in a meta position relative        to Q;    -   ee)aryl is a phenyl group;    -   ff) A compound of Formula I that selectively modulates a delta        receptor;    -   gg) A compound of Formula I that is a PPAR coagaonist that        modulates a gamma receptor and a delta receptor;    -   hh) A compound of Formula I for use in the treatment of        cardiovascular disease;    -   ii) A compound of Formula I for use in the treatment of Syndrome        X;    -   jj) A compound of Formula I for use in the control of obesity;    -   kk) A compound of Formula I for use in treating diabetes.

Synthesis

Compounds of the present invention have been formed as specificallydescribed in the examples. Further, many compounds are prepared as moregenerally as shown in the following schematics. Alternative synthesismethods may also be effective and known to the skilled artisan.

For example, an intermediate like A is alkylated with an alkyl halidelike agent B in the presence of a base (e.g. K2CO3, Cs2CO3 etc.).Hydrolysis in the presence of aqueous NaOH or LiOH gave the acidproduct.

Alternatively, an intermediate like A is coupled with an alcohol C underMitsunobu reaction condition (DEAD/PPh3, ADDP/Pbu3 etc.). Hydrolysis inthe presence of aqueous NaOH or LiOH gave the acid product:

For the compounds with nitrogen in the linker, reductive aminationprotocol is used, for example:

Suzuki coupling or Stille coupling reactions are used for the biarylcompound synthesis:

EXEMPLIFICATION

The Examples provided herein are illustrative of the invention claimedherein and are not intended to limit the scope of the claimed inventionin any way.

Instrumental Analysis

Infrared spectra are recorded on a Perkin Elmer 781 spectrometer. ¹H NMRspectra are recorded on a Varian 400 MHz spectrometer at ambienttemperature. Data are reported as follows: chemical shift in ppm frominternal standard tetramethylsilane on the δ scale, multiplicity(b=broad, s=singlet, d=doublet, t=triplet, q=quartet, qn=quintet andm=multiplet), integration, coupling constant (Hz) and assignment. ¹³CNMR are recorded on a Varian 400 MHz spectrometer at ambienttemperature. Chemical shifts are reported in ppm from tetramethylsilaneon the δ scale, with the solvent resonance employed as the internalstandard (CDCl₃ at 77.0 ppm and DMSO-d₆ at 39.5 ppm). High resolutionmass spectra are obtained on VG ZAB 3F or VG 70 SE spectrometers.Analytical thin layer chromatography is performed on EM Reagent 0.25 mmsilica gel 60-F plates. Visualization is accomplished with UV light.

Preparation 1 3-Oxo-5-phenyl-pentanoic acid ethyl ester

Ethyl acetoacetate (2.32 g, 20 mmol) is added to a pre-cold solution ofLDA (2.0 M, 20 mL, 40 mmol) in THF (100 mL) at 0° C. After addition, themixture is stirred for 30 min, then benzyl bromide (3.42 g, 20 mmol) isadded dropwise. After stirred at 0° C. for 30 min, the reaction isquenched by 5 N HCl, extracted with ethyl ether. The combined organiclayers are washed with water and brine until it is neutral.Concentration and column chromatography gave 1.6 g of the titlecompounds.

The following compounds are made in a similar manner:

Preparation 2 5-(2-Chloro-6-fluoro-phenyl)-3-oxo-pentanoic acid ethylester

Preparation 3 3-Oxo-hept-6-enoic acid ethyl ester

Preparation 4 2-Chloro-3-Oxo-5-phenyl-pentanoic acid ethyl ester

To a solution of 3-oxo-5-phenyl-pentanoic acid ethyl ester (1.6 g, 7.76mmol) in methylene chloride (18 mL) is added sulfuryl chloride (1.15 g,8.53 mmol) dropwise. After stirred at room temperature for 6 hours, thereaction mixture is poured into water, extracted with methylenechloride, washed wwashed water and brine, dried over sodium sulfate.Concentration gave the crude title compounds, which is used for the nextstep without further purification.

The following compounds are made in a similar manner:

Preparation 5 5-(2-Chloro-6-fluoro-phenyl)-2-chloro-3-oxo-pentanoic acidethyl ester

Preparation 6 2-Chloro-3-oxo-hept-6-enoic acid ethyl ester

Preparation 7 2-Chloro-3-oxo-heptanoic acid ethyl ester

Preparation 8 2-Chloro-3-oxo-hexanoic acid ethyl ester

Preparation 9 2-Chloro-4-methyl-3-oxo-pentanoic acid ethyl ester

Preparation 10 2-Chloro-4,4-dimethyl-3-oxo-pentanoic acid ethyl ester

Preparation 11 2-Chloro-3-oxo-3-phenyl-propionic acid ethyl ester

Preparation 12 2-(4-Bromo-phenyl)-4-methyl-thiazole-5-carboxylic acidethyl ester

4-Bromo-thiobenzamide (5 g) in toluene is heated at reflux for 1 h in aflask equipped with a Dean-Stark trap. The dry 4-bromo-thioamide (3.4 g,15 mmol) and ethyl 2-chloroacetoacetate (2.71 g, 16.4 mmol) are heatedin ethanol (1000 mL) for overnight. The cooled reaction is concentratedand purified by short path chromatrography. The fractions that containedpure product are concentrated to yield 1.5 g (30.6%) ester as a solid.

Th following thiazoles are made in a similar manner:

Preparation 134-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethylester

Preparation 144-Isoproyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethylester

Preparation 154-Propyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethylester

Preparation 164-Butyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethylester

Preparation 174-But-3-enyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acidethyl ester

Preparation 184-tert-Butyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acidethyl ester

Preparation 194-Phenethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acidethyl ester

Preparation 204-[2-(2-Chloro-6-fluoro-phenyl)-ethyl]-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylicacid ethyl ester

Preparation 214-Phenyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethylester

Preparation 224-Phenoxymethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acidethyl ester

Step A 4-Bromomethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylicacid ethyl ester

4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethylester (1.6 g, 5.00 mmol) is dissolved into chloroform (50 mL) thenN-bromosuccinimide (1.0 g, 5.5 mmol) and 2,2′-azobisisobutyronitrile(0.412 g, 2.5 mmol) are added and the reaction is heated to reflux. Thereaction is monitored by TLC until no starting material remained. Thereaction is allowed to cool to room temperature, then diluted with morechloroform (100 mL). Water (50 mL) is added and the two phases areseparated. The organic layer is washed with brine, then dried overanhydrous sodium sulfate. The material is then concentrated and furtherpurified using flash column chromatography to yield 1.97 g or 99% yield.

Step B4-Phenoxymethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acidethyl ester

Phenol (0.518 g, 5.5 mmol) is combined with anhydrous acetonitrile (20mL) and cesium carbonate (2.3 g, 10 mmol) and allowed to stir at roomtemperature under nitrogen. To the reaction is added4-bromomethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acidethyl ester (1.97 g, 5.00 mmol). The reaction is monitored by TLC untilall of the bromide is consumed. The reaction is diluted with ethyl ether(100 mL), then o.1N NaOH (50 mL) is added. The two phases are separated,then the organic layer is washed with water (50 mL) and brine (50 mL).The organic layer is dried over anhydrous sodium sulfate, thenconcentrated. The material is further purified using flashchromatography to yield 1.75 g or 86% yield of the product.

The following compounds are made in a similar manner:

Preparation 234-(3,5-Bis-trifluoromethyl-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylicacid ethyl ester

Preparation 244-(2-Chloro-6-fluoro-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylicacid ethyl ester

Preparation 254-(4-Bromo-phenylsulfanylmethyl)-2-(4-trifluoromethyl-Phenyl)-thiazole-5-carboxylicacid ethyl ester

Preparation 264-Phenylsulfanylmethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylicacid ethyl ester

Preparation 27[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol

A THF (60 mL) solution of4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethylester (14.9 g, 47.3 mmol) is cooled to 0° C. and a 1M LiAlH₄ (47.3 mL,47.3 mmol) is added slowly. The reaction is warmed to room temperatureslowly, after stirring at room temperature for 2 h, tlc (15%EtOAc/hexane) showed that all the starting ester had been consumed. Thereaction is cooled and carefully quenched with 2.4 mL water, 2.4 mL 5NNaOH and 7 mL water. The light tan solid is filter through celite anddried to give 7.70 g crude product. Recrystallization from methanol gavepure alcohol.

The following compounds are made in a similar manner:

Preparation 28 [4-Methyl-2-(4-bromo-phenyl)-thiazol-5-yl]-methanol

Preparation 29[4-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol

Preparation 30[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol

Preparation 31[4-Propyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol

Preparation 32[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol

Preparation 33[4-But-3-enyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol

Preparation 34[4-tert-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol

Preparation 354-Phenethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol

Preparation 364-[2-(2-Chloro-6-fluoro-phenyl)-ethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol

Preparation 37[4-Phenyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol

Preparation 38[4-Phenoxymethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol

Preparation 39[4-(2-Chloro-6-fluoro-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol

Preparation 40[4-(3,5-Bis-trifluoromethyl-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol

Preparation 41[4-Phenylsulfanylmethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol

Preparation 42[4-(4-Bromo-phenylsulfanylmethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol

Preparation 435-Chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole

A solution of[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol (1.03 g,3.75 mmol) and triethyl amine (1.05 mL, 7.5 mmol) in methylene chloride(15 mL) is cooled to 0° C., then MeSO2Cl is added dropwise. After 2 hrs,TLC indicated that the reaction is not complete, 10 mol % more oftriethyl amine and MeSO₂Cl are added. After additional 2 hrs, thereaction mixture is diluted with methylene chloride and washed withsodium bicarbonate, water and brine, dried over sodium sulfate.Concentration gave the crude title compound, which is used for the nextstep without further purification.

The following compounds are made in a similar manner:

Preparation 44 5-Chloromethyl-4-methyl-2-(4-bromophenyl)-thiazole

Preparation 455-Chloromethyl-4-isopropyl-2-(4-trifluoromethyl-phenyl)-thiazole

Preparation 465-Chloromethyl-4-propyl-2-(4-trifluoromethyl-phenyl)-thiazole

Preparation 475-Chloromethyl-4-butyl-2-(4-trifluoromethyl-phenyl)-thiazole

Preparation 484-But-3-enyl-5-chloromethyl-2-(4-trifluoromethyl-phenyl)-thiazole

Preparation 495-Chloromethyl-4-tert-butyl-2-(4-trifluoromethyl-phenyl)-thiazole

Preparation 505-Chloromethyl-4-phenethyl-2-(4-trifluoromethyl-phenyl)-thiazole

Preparation 515-Chloromethyl-4-[2-(2-Chloro-6-fluoro-phenyl)-ethyl]-2-(4-trifluoromethyl-phenyl)-thiazole

Preparation 52 5-Chloromethyl-4-phenoxymethyl-2-(4-trifluoromethylphenyl)-thiazole

Preparation 534-(2-Chloro-6-fluoro-phenoxymethyl)-5-chloromethyl-2-(4-trifluoromethyl-phenyl)-thiazole

Preparation 544-(3,5-Bis-trifluoromethyl-phenoxymethyl)-5-chloromethyl-2-(4-trifluoromethyl-phenyl)-thiazole

Preparation 555-Chloromethyl-4-phenylsulfanylmethyl-2-(4-trifluoromethyl-phenyl)-thiazole

Preparation 564-(4-Bromo-phenylsulfanylmethyl)-5-chloromethyl-2-(4-trifluoromethyl-phenyl)-thiazole

Preparation 575-Chloromethyl-4-ethyl-2-(4-trifluoromethyl-phenyl)-thiazole

Preparation 582-(3,5-Bis-trifluoromethyl-phenyl)-5-chloromethyl-4-methyl-thiazole

Step A

To a solution of 2-Bromo-4-methyl-thiazole-5-carboxylic acid methylester (0.850 g, 3.39 mmol) in toluene:ethanol (1:1) (30 mL) at roomtemperature under nitrogen is added 3,5-bistrifluormethylbenzene boronicacid (1.0 g, 3.74 mmol). The reaction is purged of air and flushed withnitrogen a few times, followed by addition of tetrakistriphenylphosphine palladium (0.200 g, 0.17 mmol) and sodium carbonate(2.7 mL, 2.5M soln., 6.8 mmol). The reaction is purged again, thenheated to reflux under nitrogen and monitored by TLC. After completeconsumption of the starting material, the reaction is allowed to cool toroom temperature, then diluted with ethyl acetate, celite added,filtered, and the two phases are separated. The organic layer is washed,dried, filtered and concentrated. The crude2-(3,5-Bis-trifluoromethyl-phenyl)-4-methyl-thiazole-5-carboxylic acidmethyl ester (0.545 g, 1.42 mmol), 42% yield, is further purified usingflash column chromatography.

Step B

2-(3,5-Bis-trifluoromethyl-phenyl)-4-methyl-thiazole-5-carboxylic acidmethyl ester (0.545 g, 1.42 mmol), is dissolved in anhydroustetrahydrofuran (6 mL) and cooled to 0° C. with stirring under nitrogen.Lithium aluminumhydride, 1.0M in THF, (1.40 mL, 1.40 mmol) is added andthe reaction is monitored by TLC. After the starting material iscompletely consumed, the reaction is quenched with water, base, morewater, and celite added, followed by dilution with ether. The mixture isfiltered through a plug of celite and the two phases are separated. Theorganic layer is washed with water and brine, dried over sodium sulfate,then concentrated. The residue is further purified using flash columnchromatography. The[2-(3,5-Bis-trifluoromethyl-phenyl)-4-methyl-thiazol-5-yl]-methanol(0.460 g, 1.35 mmol) is formed in 95% yield.

Step C

[2-(3,5-Bis-trifluoromethyl-phenyl)-4-methyl-thiazol-5-yl]-methanol(0.460 g, 1.35 mmol), is dissolved in anhydrous dichloromethane (6 mL)and cooled to 0° C. with stirring under nitrogen. Triethyl amine (0.350mL, 2.60 mmol) and methane sulfonyl chloride (0.200 mL, 2.0 mmol) areadded and the reaction is monitored by TLC. After the starting materialis completely consumed, the reaction is diluted with dichloromethane andextracted against saturated sodium bicarbonate solution. The two phasesare separated and the organic layer is washed with water and brine,dried over sodium sulfate, then concentrated. The residue is furtherpurified using flash column chromatography. The2-(3,5-Bis-trifluoromethyl-phenyl)-5-chloromethyl-4-methyl-thiazole isformed quantitatively and used without further purification.

Preparation 59 4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazole-5-carboxylicacid methyl ester

To a solution of 4-trifluoromethyl benzoic acid (0.100 g, 0.239 mmole)in methanol (2.0 mL), is added sodium hydroxide (0.093 g, 0.287 mmole)and stirred at room temperature for 2 hours. The mixture is concentratedto dryness in vacuo to give sodium 4-trifluoromethyl-benzoate as a whitesolid. It is then mixed with NH₄OAc (8.32 g, 107.9 mmole) in glacialacetic acid (500 mL) and heated at 100° C. for 16 hours. After removedthe solvents on rota-vapor, the residue is partitioned between ethylacetate (300 mL) and saturated sodium bicarbonate (300 mL). Extractedthe aqueous layer with ethyl acetate (300 mL) one more time. Thecombined organic is ish with brine (3×500 mL), dried over Na₂SO₄,filtered and concentrated. The crude product is purified bychromatography on silica gel column, gradient elute with 0 to 10% ethylacetate in hexane and concentrated to provide the titled compound as awhite solid. Mass [EI+] 300 (M⁺+H).

Preparation 60[4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-methanol

To a solution of4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazole-5-carboxylic acid methylester (4.63 g, 15.47 mmole) in THF (100 mL), is added LiBH₄ in oneportion at 0° C. The reaction is warmed up to room temperature andstirred for an hour. Additional LiBH₄ is added and the reaction isheated at 60° C. for 30 minutes. The excess amount of LiBH₄ is destroyedusing 6N HCl (50 mL) dropwise at 0° C. The mixture is partitionedbetween ethyl acetate (300 mL) and brine (300 mL). The organic layer iswashed with brine (3×300 mL), dried over Na₂SO₄, filtered andconcentrated. The crude product is purified by flash chromatography,eluting with 60% ethyl acetate in hexane and concentrated to provide thetitled compound as a white solid. Mass [EI+] 272 (M+H)⁺.

Preparation 61[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-methanol

Step 1 2-(4-tert-Butyl-benzoylamino)-propionic acid methyl ester

D, L Alanine methyl ester (18.5 g, 132 mmol), triethylamine (42 mL, 300mmol) and dichloromethane (300 mL) are stirred in an ice/water bath.4-(Trifluromethyl)benzoyl chloride (25 g, 120 mmol) is added dropwiseand the resulting mixture is allowed to stir for 20 hr at roomtemperature. 500 mL water and 100 mL 1M hydrochloric acid aresuccessively added. The organic layer is separated, washed with 250 mLeach of saturated sodium hydrogen carbonate, water, and brine, driedover anhydrous magnesium sulfate, filtered, and concentrated to 100 mLvolume. The mixture is diluted with 200 mL hexanes, cooled to 0° C. for1 hr, and the white solid filtered and dried under vacuum to afford2-(4-tert-Butyl-benzoylamino)-propionic acid methyl ester, 26.5 g, 80%.MS (ES): 276 (M⁺+1).

Step 2 2-(4-tert-Butyl-benzoylamino)-propionic acid

A mixture of 2-(4-tert-Butyl-benzoylamino)-propionic acid methyl ester(26.3 g, 95.6 mmol), 200 mL 1M sodium hydroxide, and 100 mLtetrahydrofuran is stirred at room temperature 20 hr. The resultingclear solution is cooled on an ice/water bath and the pH is adjusted to2 with concentrated hydrochloric acid. The product is extracted withthree 250 mL portions of ethyl acetate. The combined extracts are washedwith 100 mL each of water and brine, dried over anhydrous magnesiumsulfate, filtered, and concentrated to afford2-(4-tert-Butyl-benzoylamino)-propionic acid as a white solid, 24.6 g,95%. MS M⁺+1 260.

Step 3 [4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-methanol

To a solution of 2-(4-Trifluoromethyl-benzoylamino)-propionic acid (33.4g, 128 mmol) is added oxalyl chloride (111 mL, 1.27 Mol) and 1 drop ofDMF and the solution stirred overnight. The volatiles are removed invacuo and toluene (20 mL) is added. The toluene is then removed invacuo. To the resultant crude oil is dissolve in 50 mL methylenechloride, cooled to 0° C. and triethylamine (27 mL, 192 mmol) is addedfollowed by methanol (50 mL). After 3 hrs the volatiles are removed invacuo and the crude oil is purified by flash column chromatography(20%-50% ethyl acetate/hexanes) to provide 12.6 g (35%) of4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazole-5-carboxylic acid methylester. This ester (2.0 g, 7.0 mmol) is reduced to the alcohol bydissolution in THF (50 mL) and adding 4 eq. LiBH₄ (0.610 g, 28.0 mmol)to provide 1.8 g (100%)[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-methanol. MS M⁺+1258.

Preparation 622-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethanol

Prepration 632-[5-Propyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethanol

Preparation 64 Toluene-4-sulfonic acid2-[5-propyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethyl ester

Step A

3-Oxo-heptanoic acid methyl ester (25 g, 0.157 Mol) is dissolved intoanhydrous dichloromethane (DCM) (200 mL) and then cooled to 0° C.-5° C.while stirring. A solution of bromine (25.25 g, 0.160 Mol) in DCM (50mL) is added dropwise over 2 h. to the solution of the beta keto-ester.After the addition, the mixture is allowed to stir 0.5 h. at 0° C., thenthe ice bath is removed and the mixture is allowed to stir at roomtemperature for 18 h. TLC will show complete consumtion of startingmaterial, then ice water (200 g) is added with stirring. The organiclayer is collected and washed with cold water (2×) and brine. Thefiltered solution is dried over anhydrous sodium sulfate, thenconcentrated to a clear liquid. The crude 4-Bromo-3-oxo-heptanoic acidmethyl ester (31.5 g, 0.135 Mol), 86% yield, is used without furtherpurification.

Step B

4-Bromo-3-oxo-heptanoic acid methyl ester (6.0 g, 25.0 mmol) isdissolved into denatured ethanol (100 mL) and para-trifluoromethylthiobenzamide (5.0 g, 24.4 mmol) is added in one portion. The reactionis purged of air and flushed with nitrogen then heated to reflux. Thereaction is monitored by TLC and HPLC and when complete, the reaction isallowed to cool to room temperature. The solvent is removed and thereaction is diluted with ethyl acetate (200 mL), followed by ishes withsaturated sodium bicarbonate solution, water, and brine. The ethylacetate solution is dried over anhydrous sodium sulfate, thenconcentrated add further purified using flash column chromatography (10%EtOAc/Hexanes) to yield pure[[5-Propyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-acetic acid methylester (8.66 g, 24.2 mmol) or 98% yield.

Step C

[[5-Propyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-acetic acid methylester (8.66 g, 24.2 mmol) is dissolved into anhydrous tetrahydrofuran(THF) (100 mL) and then cooled to 0° C. with stirring. Lithium aluminumhydride (24.2 mL, 1M in THF, 24.2 mmol) is slowly added by syringe andthe reaction is monitored by TLC. Upon complete conversion, the reactionis carefully quenched using water, base, and water. Celite is added tothe reaction, followed by diethyl ether and the mixture is then filteredthrough a celite plug. The two phases are then separated and the organiclayer is washed using water and brine. The organic layer is the driedover anhydrous sodium sulfate and concentrated. The pure2-[5-Propyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethanol (5.739 g,18.2 mmol) is obtained in 75% yield after flash column chromatography.

Step D

The 2-[5-Propyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethanol(5.739 g, 18.2 mmol) is dissolved into anhydrous dichloromethane (DCM)(100 mL) and dimethylamino pyridine (0.670 g, 5.46 mmol), tosicanhydride (11.9 g, 36.4 mmol), and pyridine (5 mL, 64 mmol) are added atroom temperature. The reaction is monitored by TLC, and upon completeconsumption of the starting alcohol, the reaction is diluted with DCMand extracted against saturated sodium bicarbonate solution. The organiclayer is washed with water and brine, then dried over anhydrous sodiumsulfate and concentrated. The pure Toluene-4-sulfonic acid2-[5-propyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethyl ester (4.46g, 9.5 mmol) is obtained after flash column chromatography.

The following compounds are prepared in a similar manner:

Preparation 65 Toluene-4-sulfonic acid2-[5-ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethyl ester

Preparation 66 Toluene-4-sulfonic acid2-[2-(2-chloro-phenyl)-5-ethyl-thiazol-4-yl]-ethyl ester

Preparation 67 2-(4-Hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid

Step A 2-(4-Benzyloxy-2-formylphenoxy)-2-methyl propionic acid ethylester

5-Benzyloxy-2-hydroxy-benzaldehyde (Kappe, T.; Witoszynskyj, T. Arch.Pharm., 1975, 308 (5), 339-346) (2.28 g, 10.0 mmol), ethylbromoisobutyrate (2.2 mL, 15 mmol), and cesium carbonate (3.26 g, 10.0mmol) in dry DMF (25 mL) are heated at 80° C. for 18 h. The reactionmixture is cooled and partitioned between water (30 mL) and ether (75mL). The organic layer is washed with brine (15 mL). The aqueous layersare back-extracted with ethyl acetate (30 mL), and the organic layer iswashed with brine (20 mL). The combined organic layers are dried(Na₂SO₄) and concentrated to a brown oil. The crude product is purifiedby flash chromatography using hexanes:ethyl acetate (2.5:1) to give apale yellow solid (3.04 g, 89%): mp 65° C.; ¹H NMR (400 MHz, CDCl₃) δ1.24 (t, 3H, J=7.1 Hz), 1.62 (s, 6H), 4.23 (q, 2H, J=7.1 Hz), 6.81 (d,1H, J=8.8 Hz), 7.10 (dd, 1H, J=4.6, 9.0 Hz), 7.30-7.43 (m, 6H); MS (ES)m/e 343.1 [M+1].

Step B 2-(4-Hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethylester

2-(4-Benzyloxy-2-formyl-phenoxy)-2-methyl-propionic acid ethyl ester(9.00 g, 26.3 mmol) in ethanol (250 mL) is treated with 5% Pd/C (1.25 g)and hydrogen (60 psi, rt, overnight). Additional 5% Pd/C (1.25 g) isadded, and the reaction is continued for 6 h at 40° C. The mixture isfiltered and concentrated to a tan oil (6.25 g). This oil contained 9mol % of 2-(4-Hydroxy-2-hydroxymethyl-phenoxy)-2-methyl-propionic acidethyl ester. ¹H NMR (400 MHz, CDCl₃) δ 1.26 (t, 3H, J=7.3 Hz), 1.51 (s,6H), 2.14 (s, 3H), 4.24 (q, 2H, J=7.3 Hz), 5.68 (brs, 1H), 6.47 (dd, 1H,J=3.4, 8.8 Hz), 6.59 (d, 1H, J=8.3 Hz), 6.60 (brs, 1H).

The following compound is prepared in a similar manner:

Preparation 68 2-(4-Hydroxy-2-methyl-phenoxy)-acetic acid

¹H NMR (400 MHz, CDCl3) δ 1.28 (t, 3H, J=7.1 Hz), 2.24 (s, 3H), 4.25 (q,2H, J=7.1 Hz), 4.55 (s, 2H), 6.56 (dd, 1H, J=2.7, 8.5 Hz), 6.61 (d, 1H,J=8.3 Hz), 6.65 (d, 2H, J=2.9 Hz).

Preparation 69 (4-Hydroxy-2-propyl-phenoxy)-acetic acid ethyl ester

Step A 4-Benzyloxy-2-propylphenol

2-Allyl-4-benzyloxyphenol (WO 9728137 A1 19970807, Adams, A. D. et al.)(5.00 g, 20.8 mmol) in ethyl acetate (40 mL) is treated with 5% Pd/C(0.25 g) and hydrogen (1 atm) at ambient temperature for 18 h. Themixture is filtered and concentrated. The crude product is purified on aBiotage medium pressure chromatography system using a 40 L normal phasecartridge and eluted with 10% ethyl acetate in hexanes to give a tansolid (2.8 g, 56%). Rf=0.33 (25% EtOAc/Hexanes); ¹H NMR (400 MHz, CDCl₃)δ 7.44-7.31 (m, 5H), 6.78 (s, 1H), 6.69 (d, J=1.5 Hz, 2H), 5.00 (s, 2H),4.31 (s, 1H), 2.55 (t, J=7.6 Hz, 2H), 1.64 (q, J=7.5 Hz, 2H), 0.97 (t,J=7.3 Hz, 3H).

Step B (4-Benzyloxy-2-propylphenoxy)acetic acid ethyl ester

A solution of 4-benzyloxy-2-propylphenol (0.50 g, 1.94 mmol) in dry DMF(7 mL) is cooled in an ice bath and treated with NaH (0.15 g, 3.8 mmol,60% oil dispersion). The ice bath is removed, ethyl bromoacetate (0.43mL, 3.9 mmol) is added, and the mixture is placed in an oil bath (T=85°C.). After 18 h, the reaction mixture is cooled and concentrated invacuo. The residue is diluted with EtOAc, washed with brine (2×), dried(Na₂SO₄), and concentrated. The crude product is purified by radialchromatography using 10% ethyl acetate in hexanes to give a tan solid(0.62 g, 97%). ¹H NMR (400 MHz, CDCl₃) δ 7.44-7.31 (m, 5H), 6.82 (d,J=2.9 Hz, 1H), 6.72 (dd, J=8.8, 2.9 Hz, 1H), 6.66 (d, J=8.8 Hz, 1H),5.00 (s, 2H), 4.57 (s, 2H), 4.25 (q, J=7.0 Hz, 2H), 2.63 (t, J=7.6 Hz,2H), 1.64 (q, J=7.5 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H), 0.95 (t, J=7.3 Hz,3H); MS (FIA) m/e 329 (M+1).

Step C (4-Hydroxy-2-propylphenoxy)acetic acid ethyl ester

A solution of (4-benzyloxy-2-propylphenoxy)acetic acid ethyl ester (0.60g, 1.83 mmol) in THF (15 mL) is treated with 5% Pd/C (75 mg) andhydrogen (60 psi) at ambient temperature for 24 h. The mixture isfiltered and concentrated. The crude product is purified by radialchromatography using 15% ethyl acetate in hexanes to give a tan solid(0.25 g, 57%). ¹H NMR (400 MHz, CDCl₃) δ 6.66 (d, J=2.9 Hz, 1H), 6.62(d, J=8.8 Hz, 1H), 6.57 (dd, J=8.8, 2.9 Hz, 1H), 4.56 (s, 1H), 4.40 (s,1H), 4.25 (q, J=7.2 Hz, 2H), 2.61 (t, J=7.6 Hz, 2H), 1.63 (q, J=7.5 Hz,2H), 1.29 (t, J=7.1 Hz, 3H), 0.95 (t, J=7.3 Hz, 3H); MS (FIA) m/e 239(M+1).

Preparation 70 (3-Bromo-4-hydroxy-phenoxy)-acetic acid ethyl ester

To a solution of (4-hydroxy-phenoxy)-acetic acid ethyl ester (0.59 g, 3mmol) in acetic acid (1.5 mL) is added bromine (0.48 g, 9 mmol) inacetic acid (0.5 mL) at room temperature. After 5 min, solvent isevaporated and purified by column chromatography on silica gel givingthe title compound (0.6 g).

Preparation 71 (4-Mercapto-phenoxy)-acetic acid ethyl ester

Step A (4-Chlorosulfonyl-phenoxy)-acetic acid ethyl ester

Phenoxy-acetic acid ethyl ester (9.1 mL) is added to chlorosulfonic acid(15 mL) at 0° C. dropwise. The reaction is stirred at 0° C. for 30 min,it is allowed to warm to room temperature. After 2 hrs, the reactionmixture is poured into ice, solid product is collected by filtration anddried under vacuum.

Step B (4-Mercapto-phenoxy)-acetic acid ethyl ester

To a mixture of (4-chlorosulfonyl-phenoxy)-acetic acid ethyl ester (0.98g, 3.5 mmol) and tin powder (2.1 g) in ethanol (4.4 mL) is added HCl indioxane (1.0 M, 4.4 mL) under nitrogen. The mixture is heated to refluxfor 2 hrs, it is poured into ice and methylene chloride and filtered.The layers are separated and extracted with methylene chloride, driedand concentrated. The crude product is used for next step withoutpurification.

The following compounds are made in a similar manner:

Preparation 72 (4-Mercapto-2-methyl-phenoxy)-acetic acid ethyl ester

This compound can also be made by the following procedure: To a stirredsuspension of Zn powder (10 μm, 78.16 g, 1.2 mol) and dichlorodimethylsilane (154.30 g, 145.02 mL, 1.2 mol) in 500 mL of dichloroethane isadded a solution of (4-chlorosulfonyl-2-methyl-phenoxy)-acetic acidethyl ester (100 g, 0.34 mol) and 1,3-dimethylimidazolidin-2-one (116.98g, 112.05 mL, 1.02 mol) in 1 L of DCE. Addition is at a rate so as tomaintain the internal temperature at ˜52° C., cooling with chilled wateras necessary. After addition is complete, the mixture is heated at 75°C. for 1 hour. It is then cooled to room temperature, filtered andconcentrated iv. Add MTBE, washed twice with saturated LiCl solutionconcentrate iv again. Take up the residue in CH₃CN, ish with hexane (4×)and concentrate iv to yield a biphasic mixture. Let stand in aseparatory funnel and separate layers, keeping the bottom layer forproduct. Filtration through a plug of silica gel (1 Kg, 25%EtOAc/hexane) and subsequent concentration yielded 61 g (79%) of aclear, colorless oil.

NMR (DMSO-d₆) δ 7.1 (s, 1H), 7.05 (dd, 1H), 6.75 (d, 1H), 5.03 (s, 1H),4.75 (s, 2H), 4.15 (q, 2H), 2.15 (s, 3H), 1.2 (t, 3H).

Preparation 73 (4-Mercapto-2-propyl-phenoxy)-acetic acid ethyl ester

Preparation 74 3-(4-Mercapto-2-methyl-phenyl)-propionic acid methylester

Step A 3-(4-Dimethylthiocarbamoyloxy-2-methyl-phenyl)-propionic acidmethyl ester

3-(4-Hydroxy-2-methyl-phenyl)-propionic acid methyl ester (5.0 g, 25.75mmol) is dissolved into dry dioxane (100 mL) and combined with4-dimethylamino pyridine (0.500 g, 2.6 mmol), triethylamine (7.0 mL,51.5 mmol), and dimethylaminothiocarbomoyl chloride (4.5 g, 32.17 mmol).The reaction is heated to reflux under nitrogen. The reaction ismonitored by TLC until all of the phenol is consumed, 20 h. Aftercooling to room temperature, the reaction is diluted with ethyl acetate(200 mL). Water (75 mL) is added and the two layers are separated. Theorganic layer is washed with brine (75 mL) then dried over anhydroussodium sulfate. The solvent is removed and the residue is dried undervacuum.

Step B 3-(4-Dimethylcarbamoylsulfanyl-2-methyl-phenyl)-propionic acidmethyl ester

3-(4-Dimethylthiocarbamoyloxy-2-methyl-phenyl)-propionic acid methylester, taken crude from the previous step, is diluted with 75 mL oftetradecane and heated to reflux under nitrogen. The reaction ismonitored by TLC until all the conversion is complete, 20 h. Thereaction is allowed to cool to room temperature, then the tetradecane isdecanted away from the resulting oil. The residue is rinsed severaltimes with hexanes. This oil is then purified using flash columnchromatography, yielding 5.01 g, or 69% (2 steps) of the product.

Step C 3-(4-Mercapto-2-methyl-phenyl)-propionic acid methyl ester

3-(4-Dimethylcarbamoylsulfanyl-2-methyl-phenyl)-propionic acid methylester (5.01 g, 17.8 mmol) is diluted with methanol (30 mL) and to thisis added sodium methoxide (1.7 mL of 4M in methanol, 7.23 mmol). Thereaction is heated to reflux under nitrogen and monitored by TLC. Aftercomplete conversion, 20 h., the reaction is allowed to cool to roomtemperature. The reaction is neutralized with 1N HCl (7.23 mL) anddiluted with ethyl acetate (150 mL). The two phases are separated andthe organic layer is washed with water (75 mL), then brine (75 mL). Theorganic layer is then dried over anhydrous sodium sulfate, thenconcentrated to yield 4.43 g crude product that is used without furtherpurification.

Preparation 75 4-(2-Methoxycarbonyl-ethyl)-3-methyl-benzoic acid

Step A 4-Bromo-3-methyl-benzoic acid benzyl ester

To a solution of 4-Bromo-3-methyl-benzoic acid benzyl (25.3 g, 0.118mol) in DMF (200 mL) is added Cs2CO3 (76.6 g, 0.235 mol), followed bybenzyl bromide (15.4 mL). After stirred at room temperature for 2 h, thereaction mixture is diluted with ethyl acetate, filtered through celite.The filtrate is washed with water and brine, dried over sodium sulfate,concentration gave the title product.

Step B 4-(2-Methoxycarbonyl-vinyl)-3-methyl-benzoic acid benzyl ester

To a solution of 4-bromo-3-methyl-benzoic acid benzyl ester (36 g, 118mmol) in propronitrile (1000 mL) is added methyl acrylate (43.3 mL) anddiisopropylethyl amine (42 mL), the solution is degassed and filled withnitrogen for three times. To this mixture are addedtri-o-tolyl-phosphane (14.5 g) and palladium acetate (5.34 g) undernitrogen, then heated at 110° C. overnight, cooled to room temperature,filtered through celite. The solvent is evaporated, the residue is takeninto ethyl acetate and washed with water and brine, dried over sodiumsulfate. Concentration and column chromatography on silica gel elutedwith hexanes and ethyl acetate gave the title compound (31 g, 84.7%).

Step C 4-(2-Methoxycarbonyl-ethyl)-3-methyl-benzoic acid

A mixture of 4-(2-methoxycarbonyl-vinyl)-3-methyl-benzoic acid benzylester (11.6 g, 37.4 mmol) and Pd/C (5%, 1.5 g) in THF (300 mL) andmethanol (100 mL) is stirred under 60 psi of hydrogen overnight.Catalyst is filtered off, filtrate is concentrated giving the titlecompound (8.3 g, 100%).

Preparation 76 (4-Hydroxy-2-methyl-phenyl)-acetic acid methyl ester

Step A

4-Methoxy-2-methylbenzoic acid (2.5 g, 15.04 mmol) is stirred in thionylchloride (50 mL) at reflux 2 hr. The mixture is concentrated and dilutedwith toluene (10 mL) and concentrated. The resulting solid is driedunder vacuum 18 hr. The resulting acid chloride is stirred in 20 mLether at 0 deg C. A solution of diazomethane (39.6 mmol) in ether (150mL) is added to the acid chloride solution and stirred 18 hr. Theresulting diazoketone solution is concentrated. The residue is stirredin methanol (100 mL) and a solution of silver benzoate in triethylamine(1.0 g in 10 mL) is added and the reaction is heated to 60 deg C. andstirred 1 hr. The mixture is concentrated, diluted with 1.0 N aqueoushydrochloric acid (20 mL), extracted to three portions of ethyl acetate(50 mL each). The extracts are combined, washed with aqueous saturatedsodium hydrogen carbonate, water, and brine (50 mL each), dried overanhydrous magnesium sulfate, filtered and concentrated. The residue ispurified via silica gel chromatography eluting with 9:1 hexanes:ethylacetate to afford 1.5 g (51%) of the homologated ester as a white solid.

Step B

(4-Methoxy-2-methyl-phenyl)-acetic acid methyl ester (1.5 g, 7.72 mmol)is stirred in dichloromethane (50 mL) at 0 deg. C. Aluminum chloride(4.13 g, 31 mmol) is added followed by ethane thiol (2.9 mL, 38.6 mmol).The resulting mixture is stirred at room temperature for 2 hr. Water (50mL) is added and the product is extracted into ethyl acetate (3×50 ml),the extracts are combined, dried over anhydrous magnesium sulfate,filtered, and concentrated to afford the title compound as a colorlessoil, 1.4 g, 100%. MS M⁺+1 181. The structure is confirmed by ¹H NMRspectroscopy.

Preparation 77 (3-Hydroxy-phenyl)-acetic acid methyl ester

Step A (3-Hydroxy-phenyl)-acetic acid methyl ester

(3-Hydroxy-phenyl)-acetic acid (5.0 g, 32.86 mmol) is stirred inmethanol (100 mL) and concentrated (98%) sulfuric acid (3.0 mL) isadded. The mixture is heated to reflux 18 hr. The reaction is cooled andconcentrated. The residue is diluted with water (100 mL) and extractedwith ethyl acetate (3×50 mL). The combined extracts are dried overanhydrous magnesium sulfate, filtered, and concentrated to yield thetitle compound as an orange oil, 5.46 g, 100%. MS M⁺+1 167. Thestructure is confirmed by ¹H NMR spectroscopy.

The following compounds are made in a similar manner:

Preparation 78 (3-Hydroxy-4-methoxy-phenyl)-acetic acid methyl ester

An orange oil. MS M⁺+1 197. The structure is confirmed by ¹H NMRspectroscopy.

Preparation 79 3-(3-Hydroxy-phenyl)-propionic acid methyl ester

Step A 3-(3-Hydroxy-phenyl)-propionic acid methyl ester

An orange oil. MS M⁺+1 181. The structure is confirmed by ¹H NMRspectroscopy.

Preparation 80 (3-Mercapto-phenyl)-acetic acid methyl ester

Step A (3-Dimethylthiocarbamoyloxy-phenyl)-acetic acid methyl ester

A mixture of (3-Hydroxy-phenyl)-acetic acid methyl ester (5.5 g, 33.1mmol), N,N-dimethyl thiocarbamoyl chloride (5.11 g, 41.38 mmol),triethylamine (9.2 mL, 66.2 mmol), N,N-dimethylamino pyridine (0.4 g,3.31 mmol) and dioxane (50 mL) is stirred at reflux 18 hr. The mixtureis concentrated, partioned between 1M aqueous hydrochloric acid (200 mL)and ethyl acetate (3×75 mL). The combined organic extracts are driedover anhydrous magnesium sulfate, filtered, concentrated, and purifiedvia silica chromatography eluting the product with dichloromethane toafford the title compound as a brown oil, 6.8 g, 81%. MS M⁺+1 254. Thestructure is confirmed by ¹H NMR spectroscopy.

Step B (3-Dimethylcarbamoylsulfanyl-phenyl)-acetic acid methyl ester

(3-Dimethylthiocarbamoyloxy-phenyl)-acetic acid methyl ester (6.8 g,26.84 mmol) is stirred in tetradecane (30 mL) at 255 deg C. for 8 hr.The mixture is cooled, the residue is purified by silica chromatographyeluting the product with hexanes to 1:1 hexanes:ethyl acetate to affordthe title compound as an orange oil, 4.9 g, 58%. MS M⁺+1 254. Thestructure is confirmed by ¹H NMR spectroscopy.

Step C (3-Mercapto-phenyl)-acetic acid methyl ester

A mixture of (3-dimethylcarbamoylsulfanyl-phenyl)-acetic acid methylester (2.0 g, 7.9 mmol), potassium hydroxide (1.4 g, 24 mmol) methanol(50 mL), and water (5 mL) is stirred at reflux 3 hr. The mixture isconcentrated, and product partitioned between 1M aqueous hydrochloricacid (50 mL) and ethyl acetate (3×75 mL). The combined extracts aredried over anhydrous magnesium sulfate, filtered and concentrated. Theresidue is taken up in methanol (50 mL), 2 mL concentrated sulfuric acidis added, and the mixture refluxed 3 hr. The mixture is concentrated,and the residue purified by silica chromatography eluting with 7:3hexanes:ethyl acetate to afford the title compound as a pale yellow oil,1.0 g, 69%. MS M⁺+1 183. The structure is confirmed by ¹H NMRspectroscopy.

Preparation 81 3-(4-Iodomethyl-2-methyl-phenyl)-propionic acid methylester

Step A 3-(4-Hydroxymethyl-2-methyl-phenyl)-acrylic acid methyl ester

A mixture of methyl-4-bromo-3-methylbenzoate (5.7 g, 24.88 mmol),lithium aluminum hydride (29 mL, 29 mmol, 1 M solution intetrahydrofuran) and tetrahydrofuran (100 mL) is stirred in ice/waterfor 1 hr. The reaction is quenched with aqueous hydrochloric acid (50mL, 1 M). The product is extracted into ethyl acetate (3×100 mL). Thecombined extracts are dried over anhydrous magnesium sulfate, filteredand concentrated. The crude product is taken up in propionitrile (100mL). Methylacrylate (10 mL, 121.5 mmol), palladium acetate (1.12 g, 5mmol), tri-o-tolylphosphine (3.0 g, 10 mmol), and N,N-diisopropylethylamine (8.7 mL, 50 mmol) are sequentially added and the resultingreaction mixture is heated to 110 deg C. 3 hr. The mixture isconcentrated, and the residue diluted with aqueous hydrochloric acid(100 mL, 1M). The product is extracted with dichloromethane (2×100 mL)and ethyl acetate (100 mL). The combined extracts are dried overanhydrous magnesium sulfate, filtered, concentrated, and purified viasilica chromatography eluting with 7:3 hexanes:ethyl acetate to 1:1hexanes:ethyl acetate to afford the pure product as a yellow oil, 4.7 g,91%. MS M⁺+1 207. The structure is confirmed by ¹H NMR spectroscopy.

Step B 3-(4-Hydroxymethyl-2-methyl-phenyl)-propionic acid methyl ester

A mixture of 3-(4-Hydroxymethyl-2-methyl-phenyl)-acrylic acid methylester (4.7 g, 22.8 mmol), Raney nickel (0.668 g) and tetrahydrofuran(618 mL) is shaken under 60 psig. Hydrogen 24 hr. The catalyst isfiltered off, and the mixture is concentrated to afford the product as apale yellow oil, 4.3 g, 91%. The structure is confirmed by ¹H NMRspectroscopy.

Step C 3-(4-Iodomethyl-2-methyl-phenyl)-propionic acid methyl ester

A mixture of 3-(4-Hydroxymethyl-2-methyl-phenyl)-propionic acid methylester (0.62 g, 2.98 mmol), triphenyl phosphine (0.86 g, 3.27 mmol) anddichloromethane (10 mL) is stirred at room temperature. A solution ofiodine (0.83 g, 3.27 mmol) in benzene (5 mL) is added and the blackmixture is stirred at room temperature 2 hr. The brown mixture isdiluted with 10% aqueous sodium hydrogen sulfite (5 mL) and theresulting clear mixture is washed with ethyl acetate (3×50 mL). Thecombined extracts are dried over anhydrous magnesium sulfate, filteredand concentrated. The residue is purified via silica chromatographyeluting with 9:1 hexanes:ethyl acetate to afford the title compound as acrystalline ivory solid, 0.68 g, 72%. MS M⁺+1 319. The structure isconfirmed by ¹H NMR spectroscopy.

Preparation 82 (4-Bromo-2-methyl-phenoxy)-acetic acid methyl ester

Step A (4-Bromo-2-methyl-phenoxy)-acetic acid methyl ester

A mixture of 4-bromo-2-methylphenol (1.0 g, 5.35 mmol), sodium hydride(0.26 g, 6.42 mmol, 60% mineral oil), N,N-dimethylformamide (10 mL), andmethyl-2-bromoacetate (0.56 mL, 5.88 mmol) is stirred at roomtemperature 18 hr. The mixture is diluted with water (50 mL) and theproduct extracted to ethyl acetate (3×50 mL). The combined extracts aredried over anhydrous magnesium sulfate, filtered, concentrated andpurified via silica chromatography eluting with 8:2 hexanes:ethylacetate to afford title compound as a colorless oil, 1.03 g, 74%. MS M⁺259. The structure is confirmed by ¹H NMR spectroscopy.

Preparation 83 3-(4-Amino-2-methyl-phenyl)-propionic acid methyl ester

Step A 3-(2-Methyl-4-nitro-phenyl)-acrylic acid methyl ester

To a solution of 2-bromo-5-nitrotoluene (3.11 g, 14.39 mmol) inpropionitrile (105 mL) is added DIPEA (5.1 mL, 29.28 mmol). The mixtureis degassed three times. Methyl acrylate (5.2 mL, 57.74 mmol) is addedand the mixture is degassed. Tri-o-tolylphosphine (1.77 g, 5.82 mmol)and Pd(OAc)₂ (0.64 g, 2.85 mmol) are added and the mixture is degassed afinal two times followed by heating at 110° C. for 4 h. Upon cooling,the mixture is passed through Celite and the filtrate is concentrated.The residue is partitioned between Et₂O and 1N HCl. The organics arewashed with saturated NaHCO₃ and brine, and dried with Na₂SO₄. The crudematerial is purified by flash chromatography to yield the title compound(2.90 g, 91%).

Step B 3-(4-Amino-2-methyl-phenyl)-propionic acid methyl ester

A mixture of 3-(2-Methyl-4-nitro-phenyl)-acrylic acid methyl ester (1.47g, 6.64 mmol) and 5% Pd/C (0.29 g) in MeOH (100 mL) is exposed to ahydrogen atmosphere (60 psi) for 12 h. The mixture is filtered throughCelite and purified by flash chromatography to yield the title compound(0.99 g, 77%).

Preparation 84 3-(2-Methyl-4-methylaminomethyl-phenyl)-propionic acidmethyl ester TFA salt

Step A 3-(4-Formyl-2-methyl-phenyl)-propionic acid methyl ester

A mixture of 3-(4-Hydroxymethyl-2-methyl-phenyl)-propionic acid methylester (0.49 g, 2.35 mmol) and MnO₂ (0.80 g, 9.20 mmol) in chloroform (5mL) is stirred at RT for 4 days. The mixture is filtered through Celite;the Celite is washed with copious amounts of EtOAc. The filtrate isconcentrated and purified by flash chromatography to yield the titlecompound (0.29 g, 60%).

Step B 3-(2-Methyl-4-methylaminomethyl-phenyl)-propionic acid methylester trifluoroacetic acid

To a mixture of 3-(4-Formyl-2-methyl-phenyl)-propionic acid methyl ester(0.27 g, 1.31 mmol) and methylamine (2M in THF, 0.60 mL, 1.20 mmol) inanhydrous CH₂Cl₂ (10 mL) is added 4 Å molecular sieves followed byacetic acid (0.090 mL, 1.57 mmol). The mixture is stirred at RT for 1.5h. Sodium triacetoxyborohydride (0.39 g, 1.85 mmol) is added, and themixture is stirred overnight. The reaction is quenched with saturatedNaHCO₃. The organics are washed with saturated NaHCO₃ and brine, anddried with MgSO₄. Upon concentration, the mixture is purified by reversephase chromatography to yield the title compound (0.12 g, 45%).

Preparation 85 3-(4-Aminomethyl-2-methyl-phenyl)-propionic acid methylester

Step A 3-(4-Chloromethyl-2-methyl-phenyl)-propionic acid methyl ester

To a 0° C. solution of 3-(4-Hydroxymethyl-2-methyl-phenyl)-propionicacid methyl ester (1.02 g, 4.90 mmol) in anhydrous CH₂Cl₂ (15 mL) isadded triethylamine (0.75 mL, 5.38 mmol) followed by thionyl chloride(0.40 mL, 5.48 mmol). The mixture is allowed to warm to RT overnight.Water is added, and the mixture is extracted with CH₂Cl₂. The organicsare dried with MgSO₄ and concentrated. The crude material is purified byflash chromatography to yield the title compound (1.01 g, 91%).

Step B 3-(4-Azidomethyl-2-methyl-phenyl)-propionic acid methyl ester

To a solution of 3-(4-Chloromethyl-2-methyl-phenyl)-propionic acidmethyl ester (0.52 g, 2.31 mmol) in DMF (7 mL) is added sodium azide(0.25 g, 3.84 mmol). The mixture is stirred overnight. Water is added,and the mixture is extracted with EtOAc. The organics are dried withNa₂SO₄ and concentrated to yield the title compound (0.49 g, 91%). Thematerial is used without further purification.

Step C 3-(4-Aminomethyl-2-methyl-phenyl)-propionic acid methyl ester

A mixture of 3-(4-Azidomethyl-2-methyl-phenyl)-propionic acid methylester (0.20 g, 0.86 mmol) and 5% Pd/C (32 mg) in EtOH (50 mL) is exposedto a hydrogen atmosphere (60 psi) at RT overnight. Upon filtering themixture through Celite, the filtrate is concentrated to yield the titlecompound (0.14 g, 78%). The material is used without furtherpurification.

Preparation 864-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid

To a solution of4-isopropyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acidethyl ester (0.62 g, 1.80 mmol) in THF (10 mL) is added 5M NaOH (3.5 mL,17.50 mmol). The mixture is heated at 70° C. for 12 h. Upon cooling toRT, the mixture is acidified with 5M HCl and extracted with EtOAc. Theorganics are washed with water and brine, and dried with MgSO₄. Afterconcentration, the title compound is obtained (0.46 g, 81%). Thematerial is used without further purification.

The following compounds are made in a similar manner:

Preparation 87 [5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]aceticacid

Preparation 88 [2-(6-Chloro-pyridin-3-yl)-5-methyl-oxazol-4-yl]-aceticacid methyl ester

Step A

Aspartic acid methyl ester hydrochloride salt (57 g, 310 mmol) isdissolved in dichloromethane (500 mL) and cooled to 0° C. in an icewater bath. Triethylamine (75 mL, 444 mmol) is slowly added in severalportions and the mixture is allowed to stir at 0° C. Meanwhile,6-chloronicotinic acid (35 g, 222 mmol) is dissolved intodichloromethane (500 mL) with a drop of dimethylformamide and cooled to0° C. in an ice water bath. After one hour at 0° C. the ice bath isremoved and the solution allowed to warm to room temperature. Thesolvent is evaporated, the solution concentrated to about 100 mL, andthen transferred to an addition funnel. This solution is then slowlyadded to the amino acid solution over two hours at 0° C. After twohours, the ice bath is removed. Upon reaching room temperature, thereaction is complete. The reaction is acidified with concentratedhydrochloric acid. The two phases are separated and the organic layer iswashed with water and brine. The organic layer is then dried overanhydrous sodium sulfate, filtered, and concentrated. The white solid isused without further purification.

Step B

2-[(6-Chloro-pyridine-3-carbonyl)-amino]-succinic acid 4-methyl ester(222 mmol) is dissolved in ethyl acetate (300 mL) at room temperatureand pyridine (90 mL, 1.11 mol), acetic anhydride (94 mL, 1.0 mol), anddimethyl amino pyridine (3.5 g, 22.2 mmol) are added. The reaction isheated to 90° C. under nitrogen. The reaction is monitored by HPLC andupon complete consumption of the starting material, is allowed to coolto room temperature. The reaction is diluted with additional ethylacetate and the two phases are separated. The organic layer is washed afew times with 1N HCl, then saturated sodium bicarbonate solution, andfinally brine. The organic layer is then dried over anhydrous sodiumsulfate, filtered, and concentrated. The3-[(6-Chloro-pyridine-3-carbonyl)-amino]-4-oxo-pentanoic acid methylester is used in the next step without further purification.

Step C

3-[(6-Chloro-pyridine-3-carbonyl)-amino]-4-oxo-pentanoic acid methylester is dissolved in acetic anhydride (75 mL) and concentrated sulfuricacid is added in 500 uL portions five times over a four hour period. Thereaction is monitored by HPLC. The reaction is then heated to 40° C.until the starting material is consumed. The reaction is allowed toproceed at room temperature overnight. The reaction is then concentratedto dryness and purified by column chromatography. This procedure yielded(12.8 g, 48 mmol) 22% of the desired oxazole over four steps.

Preparation 89[5-Methyl-2-(6-Phenylsulfanyl-pyridin-3-yl)-oxazol-4-yl]-acetic acidmethyl ester

[2-(6-Chloro-pyridin-3-yl)-5-methyl-oxazol-4-yl]-acetic acid methylester (4.8 g, 17.98 mmol) is dissolved in anhydrous dimethylformamide(100 mL) and allowed to stir under nitrogen. Benzenethiol (2.78 mL, 27mmol) is added by syringe, followed by anhydrous cesium carbonate (12.6g, 36 mmol). The mixture is allowed to stir under nitrogen 50° C. andmonitored by HPLC. After complete consumption of strating material, thesolution is quenched with 1N sodium hydroxide solution, diluted withethyl acetate, and then enough water added to dissolve the solids. Thetwo phases are separated and the organic layer is washed with water andbrine, dried over anhydrous sodium sulfate, filtered, and concentrated.The pure [5-Methyl-2-(6-phenylsulfanyl-pyridin-3-yl)-oxazol-4-yl]-aceticacid methyl ester (4.51 g, 13.2 mmol) is isolated in 74% yield aftercolumn chromatography.

The following compound is made in a similar manner:

Preparation 90[5-Methyl-2-(6-phenylsulfanyl-pyridin-3-yl)-oxazol-4-yl]-acetic acidmethyl ester

Example 1{2-Methyl-4-[4-phenethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-phenoxy}-aceticacid

Step A{2-Methyl-4-[4-phenethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-phenoxy}-aceticacid ethyl ester

To a solution of5-chloromethyl-4-phenethyl-2-(4-trifluoromethyl-phenyl)-thiazole (190mg, 0.5 mmol) and (4-Mercapto-2-methyl-phenoxy)-acetic acid ethyl ester(100 mg, 0.44 mmol) in acetonitrile (3 mL) is added Cs2CO3 (325 mg, 1mmol). The mixture is stirred at room temperature over night, quenchedby water, extracted with ethyl acetate, dried over sodium sulfate.Column chromatography on silica gel of the crude product gave 210 mg(83.5% yield) of the title compound.

Step B{2-Methyl-4-[4-phenethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-phenoxy}-aceticacid

To a solution of{2-methyl-4-[4-phenethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-phenoxy}-aceticacid ethyl ester (210 mg, 0.37 mmol) in THF (3 mL is added LiOH (1.0 M,2 mL). After stirred at room temperature for 2 hrs, it is acidified with5 N HCl, extracted with ether, dried over sodium sulfate. Concentrationgave the title compound (200 mg). MS (ES): 544.2 (M⁺+1); the structureis also confirmed by ¹H NMR.

The following compounds are made in a similar manner, all structures areconfirmed by MS and proton NMR:

Example 2{4-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-2-propyl-phenoxy}-aceticacid

Example 3{4-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-2-methyl-phenoxy}-aceticacid

Example 4{4-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methyl-phenoxy}-aceticacid

Example 53-{4-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methyl-phenyl}-propionicacid

Example 6{4-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-propyl-phenoxy}-aceticacid

Example 7{4-[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-2-methyl-phenoxy}-aceticacid

Example 82-{4-[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionicacid

Example 9{4-[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methyl-phenoxy}-aceticacid

Example 103-{4-[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methyl-phenyl}-propionicacid

Example 113-{4-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-2-methyl-phenyl}-propionicacid

Example 12{4-[4-(3,5-Bis-trifluoromethyl-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-2-methyl-phenoxy}-aceticacid

Example 13{2-Methyl-4-[4-propyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-phenoxy}-aceticacid

Example 14{4-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-2-methyl-phenoxy}-aceticacid

Example 15{4-[4-But-3-enyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-2-methyl-phenoxy}-aceticacid

Example 163-{2-Methyl-4-[4-propyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-phenyl}-propionicacid

Example 173-{2-Methyl-4-[4-phenethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-phenyl}-propionicacid

Example 183-{2-Methyl-4-[4-phenethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-propionicacid

Example 193-{2-Methyl-4-[4-propyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxyl]-phenyl}-propionicacid

Example 203-{4-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methyl-phenyl}-propionicacid

Example 21{4-[4-(4-Bromo-phenylsulfanylmethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-2-methyl-phenoxy}-aceticacid

Example 22{4-[4-tert-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methyl-phenoxy}-aceticacid

Example 23{4-[4-tert-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-2-methyl-phenoxy}-aceticacid

Example 24-{4-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-2-methyl-phenyl}-propionicacid

Example 25{2-Methyl-4-[4-phenoxymethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-phenoxy}-aceticacid

Example 26{4-[4-[2-(2-Chloro-6-fluoro-phenyl)-ethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-2-methyl-phenoxy}-aceticacid

Example 27{4-[4-[2-(2-Chloro-6-fluoro-Phenyl)-ethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methyl-phenoxy}-aceticacid

Example 283-{4-[4-[2-(2-Chloro-6-fluoro-phenyl)-ethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methyl-phenyl}-propionicacid

Example 29{2-Methyl-4-[4-phenoxymethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenoxy}-aceticacid

Example 303-{2-Methyl-4-[4-phenoxymethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-propionicacid

Example 31{2-Methyl-4-[4-phenylsulfanylmethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-phenoxy}-aceticacid

Example 323-{2-Methyl-4-[4-phenylsulfanylmethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-propionicacid

Example 33{4-[4-(2-Chloro-6-fluoro-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-2-methyl-phenoxy}-aceticacid

Example 343-{4-[4-(2-Chloro-6-fluoro-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methyl-phenyl}-propionicacid

Example 35{4-[4-(2-Chloro-6-fluoro-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methyl-phenoxy}-aceticacid

Example 363-{4-[4-(3,5-Bis-trifluoromethyl-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methyl-phenyl}-propionicacid

Example 37{4-[4-(3,5-Bis-trifluoromethyl-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methyl-phenoxy}-aceticacid

Example 383-{4-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-2-methoxy-propionicacid

Example 39{3-Bromo-4-[4-ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenoxy}-aceticacid

Example 402-{3-Bromo-4-[4-ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenoxy}-2-methyl-propionicacid

Example 413-{4-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methoxy-phenyl}-propionicacid

Example 42{4-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenoxy}-aceticacid

Example 433-{4-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-propionicacid

Example 44(4-{2-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethylsulfanyl}-2-methyl-phenoxy)-aceticacid

Example 453-{2-Methyl-4-[4-phenoxymethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-phenyl}-propionicacid

Step 1

3-(4-Mercapto-2-methyl-phenyl)-propionic acid-methyl ester (126 mg,0.600 mmol) is dissolved into anhydrous acetonitrile (ACN) (2 mL).Cesium carbonate (326 mg, 1.00 mmol) is added to the reaction, followedby the addition of5-Chloromethyl-4-phenoxymethyl-2-(4-trifluoromethyl-phenyl)-thiazole(200 mg, 0.5211 mmol). The reaction is allowed to stir under nitrogen atroom temperature and monitored by TLC and HPLC. Upon completeconsumption of the chloride, the reaction is diluted with diethyl etherand quenched with 0.1N NaOH. The two phases are separated, then theorganic layer washed with water and brine. The organic phase is driedover anhydrous sodium sulfate and concentrated under vacuum. The residueis further purified using either EtOAc/Hexanes (1:9) or Acetone/Hexanes(1:9) gradients on silica gel chromatography to yield3-{2-Methyl-4-[4-phenoxymethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-phenyl}-propionicacid methyl ester (100 mg, 0.1796 mmol) or 30%.

Step 2

3-{2-Methyl-4-[4-phenoxymethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-phenyl}-propionicacid methyl ester (100 mg, 0.1796 mmol) is dissolved in tetrahydrofuran(1 mL) and 5N NaOH (1 mL) is added. The mixture is heated to refluxuntil the conversion is complete. Upon complete conversion, the reactionis cooled to room temperature and 5N HCl (1 mL) is added. The mixture isdiluted with diethyl ether and extracted with 1N HCl. The organic layeris washed with water and brine, then dried over anhydrous sodiumsulfate. Concentration of the solvent reveals the pure3-{2-Methyl-4-[4-phenoxymethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-phenyl}-propionicacid in near quantitative yield (93 mg, 0.170 mmol).

The following compounds are made in a substantially similar manner:

Example 463-{4-[4-[2-(2-Chloro-6-fluoro-phenyl)-ethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-2-methyl-phenyl}-propionicacid

MS (ES): 594.2(M⁺+1).

Example 473-{2-Methyl-4-[4-phenoxymethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-phenyl}-propionicacid

MS (ES): 544.2 (M⁺+1).

Example 483-{2-Methyl-4-[4-phenylsulfanylmethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-phenyl}-propionicacid

MS (ES): 560.19(M⁺+1).

Example 49{2-Methyl-4-[4-phenyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-phenoxy}-aceticacid

Example 50{2-Methyl-4-[4-phenyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenoxy}-aceticacid

Example 51(3-{2-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-aceticacid

Step 1

(3-Hydroxy-phenyl)-acetic acid methyl ester (166 mg, 1.0 mmol) isdissolved into anhydrous acetonitrile (ACN) (5 mL). Toluene-4-sulfonicacid 2-[5-ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethyl ester(432 mg, 0.950 mmol) is added to the reaction, followed by the additionof cesium carbonate (652 mg, 2.00 mmol). The reaction is allowed to stirunder nitrogen at room temperature and monitored by TLC and HPLC. Uponcomplete consumption of the tosylate, the reaction is diluted withdiethyl ether and quenched with 0.1N NaOH. The two phases are separated,then the organic layer washed with water and brine. The organic phase isdried over anhydrous sodium sulfate and concentrated under vacuum. Theresidue is further purified using either EtOAc/Hexanes (1:9) orAcetone/Hexanes (1:9) gradients on silica gel chromatography to yield(3-{2-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-aceticacid methyl ester (140 mg, 0.311 mmol) or 33%.

Step 2

3-{2-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-aceticacid methyl ester (140 mg, 0.311 mmol) is dissolved in tetrahydrofuran(1 mL) and 5N NaOH (1 mL) is added. The mixture is heated to refluxuntil the conversion is complete. Upon complete conversion, the reactionis cooled to room temperature and 5N HCl (1 mL) is added. The mixture isdiluted with diethyl ether and extracted with 1N HCl. The organic layeris washed with water and brine, then dried over anhydrous sodiumsulfate. Concentration of the solvent reveals the pure3-{2-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-aceticacid in near quantitative yield (133 mg, 0.306 mmol).

The following compounds are made in a substantially similar manner:

Example 523-(2-Methyl-4-{2-[5-propyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionicacid

MS (ES): 478.05(M⁺+1).

Example 533-(2-Methyl-4-{2-[5-propyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethylsulfanyl}-phenyl)-propionicacid

MS (ES): 494.5(M⁺+1).

Example 54(3-{2-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-aceticacid

MS (ES): 434.09(M⁺+1).

Example 55(3-{2-[5-Propyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-aceticacid

MS (ES): 450.11 (M⁺+1).

Example 56(2-Methyl-4-{2-[5-propyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethylsulfanyl}-phenoxy)-aceticacid

Example 573-{4-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-ylmethoxy]-2-methyl-phenyl}-propionicacid

Step A3-{4-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-ylmethoxy]-2-methyl-phenyl}-propionicacid methyl ester

To a solution of[4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-methanol (0.108 g,0.400 mmole) and 3-(4-Hydroxy-2-methyl-phenyl)-propionic acid methylester (0.078 g, 0.400 mmole) in toluene (2 mL) at room temperature, isadded tributylphosphine followed by a solution of1,1′-(azodicarbonyl)-dipiperidine (0.201 g, 0.8 mmole) in toluene (2mL). The reaction is stirred overnight, then diluted with hexane (10mL). The precipitate is removed through filtration and the filtrate isconcentrated, loaded to a silica gel column, eluted with ethyl acetatein hexane (0-15%) and concentrated to provide the titled compound as awhite solid. Mass [EI+] 448 (M⁺+H).

Step B3-{4-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-ylmethoxy]-2-methyl-phenyl}-propionicacid

3-{4-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-ylmethoxy]-2-methyl-phenyl}-propionicacid methyl ester (0.100 g, 0.223 mmole) is treated with a mixture ofNaOH_((aq)) (1 mL)/THF (3 mL)/MeOH (3 mL) at room temperature overnight.The organic solvents are removed on rota-vapor. The residue is dilutedwith water (10 mL), acidified to pH=2 with 6N HCl_((aq)). Theprecipitate is collected through filtration, washed with cold water (30mL) and dried to provide the titled compound as a white solid. Mass[EI+] 434 (M⁺+H), 432 (M⁺−H).

The following compounds are made in a similar manner:

Example 58{4-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-ylmethoxy]-2-methyl-phenoxy}-aceticacid

White solid, Mass [EI+] 436 (M⁺+H), 434 (M⁺−H).

Example 59{4-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-ylmethylsulfanyl]-2-methyl-phenoxy}-aceticacid

White solid, Mass [EI+] 452 (M⁺+H), 450 (M⁺−H).

Example 60{2-Methyl-4-[4-methyl-2-(4′-trifluoromethyl-biphenyl-4-yl)-thiazol-5-ylmethylsulfanyl]-phenoxy}-aceticacid

To a solution of{4-[2-(4-Bromo-phenyl)-4-methyl-thiazol-5-ylmethylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (53 mg, 0.1076 mmol) in toluene:ethanol (1:1, 2.0 mL)is added palladium tetrakis triphenylphosphine (5.0 mg, 0.0053 mmol),4-(trifluoromethyl)-phenyl boronic acid (22.5 mg, 0.1184 mmol), and asolution of sodium carbonate (0.216 mL, 1.0M in water, 0.216 mmol). Thereaction is purged with nitrogen and heated to reflux. The reaction ismonitored by HPLC, and upon completion is allowed to cool to roomtemperature. The reaction is diluted with EtOAc and then washed with0.1N sodium hydroxide, water, and brine. The organic layer is dried overanhydrous sodium sulfate, then concentrated. The product is purified byflash column chromatography. The pure ester compound is then dilutedwith THF and 1N sodium hydroxide is added. The reaction is allowed tostir at room temperature, and monitored by TLC. Upon completion, 1Nhydrochloric acid is added to neutralize the solution. The reaction isdiluted with EtOAc and then washed with water. The organic layer isdried over anhydrous sodium sulfate and concentrated to the pure acid,50 mg or 94% yield. MS (ES): 530.7 (M⁺+1), the structure is alsoconfirmed by proton NMR.

The following compounds are made in a similar manner:

Example 61{4-[2-(3′,5′-Bis-trifluoromethyl-biphenyl-4-yl)-4-methyl-thiazol-5-ylmethylsulfanyl]-2-methyl-phenoxy}-aceticacid

Example 62{4-[2-(3′-Hydroxymethyl-biphenyl-4-yl)-4-methyl-thiazol-5-ylmethylsulfanyl]-2-methyl-phenoxy}-acetic

Example 63{4-[2-(3′-Isopropyl-biphenyl-4-yl)-4-methyl-thiazol-5-ylmethylsulfanyl]-2-methyl-phenoxy}-aceticacid

Example 64{4-[2-(3′-Acetyl-biphenyl-4-yl)-4-methyl-thiazol-5-ylmethylsulfanyl]-2-methyl-phenoxy}-aceticacid

Example 65{2-Methyl-4-[4-methyl-2-(3′-trifluoromethyl-biphenyl-4-yl)-thiazol-5-ylmethylsulfanyl]-phenoxy}-aceticacid

Example 66{4-[2-(3′,5′-Dimethyl-biphenyl-4-yl)-4-methyl-thiazol-5-ylmethylsulfanyl]-2-methyl-phenoxy}-aceticacid

Example 67{2-Methyl-4-[S-methyl-2-(4′-methyl-biphenyl-4-yl)-oxazol-4-ylmethylsulfanyl]-phenoxy}-aceticacid

Example 68{4-[2-(3′,5′-Bis-trifluoromethyl-biphenyl-4-yl)-5-methyl-oxazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}-aceticacid

Example 69{4-[2-(4′-Butyl-biphenyl-4-yl)-5-methyl-oxazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}-aceticacid

Example 70{4-[2-(4′-Butyl-biphenyl-4-yl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenoxy}-aceticacid

Example 71{4-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-3-methyl-phenoxy}-aceticacid

Step A

{4-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-3-methyl-phenoxy}-aceticacid ethyl ester To a mixture of{3-Bromo-4-[4-ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenoxy}-aceticacid ethyl ester (100 mg, 0.18 mmol), methyl boronic acid (33 mg, 0.54mmol) and cesium fluoride (90 mg, 0.54 mmol) in dioxane (2 mL) is added[1,1′]-(bisdiphenylphosphino)ferrocene]-dichloridepalladium (II) complexwith methylene chloride (1:1, 29 mg) under nitrogen. The mixture isheated to 80° C. for 18 hrs, cooled to room temperature, loaded onsilica gel column. Chromatography gave the title compound (80 mg).

Step B{4-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-3-methyl-phenoxy}-aceticacid

To a solution of{4-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-3-methyl-phenoxy}-aceticacid ethyl ester (80 mg) in THF (1 mL) is added LiOH (1.0 M, 1.0 mL),after 1 hr, acidified by 5 N HCl and extracted with ethyl, dried oversodium sulfate. Concentration gave the title acid compound (80 mg). MS(ES): 452.03 (M⁺+1), the structure is also confirmed by proton NMR.

The following compounds are made in similar manner:

Example 72{4-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-3-vinyl-phenoxy}-aceticacid

MS (ES): 464.01(M⁺+1), the structure is also confirmed by proton NMR.

Example 732-{4-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-3-methyl-phenoxy}-2-methyl-propionicacid

MS (ES): 480.0(M⁺+1), the structure is also confirmed by proton NMR.

Example 74{4-[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-ylmethoxy]-2-propyl-phenoxy}-aceticacid

To a suspension of5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-oxazole (0.10 g,0.36 mmol) and Cs₂CO₃ (0.24 g, 0.72 mmol) in 2 mL acetonitrile is added(4-hydroxy-2-propyl-phenoxy)-acetic acid ethyl ester (0.09 g, 0.38mmol). The solution is stirred for 6 hrs and poured into water (10 mL)and extracted with ethyl acetate (3×15 mL). The combined organics arewashed with water (10 mL) and brine (10 mL), dried (Na₂SO₄), filteredand concentrated in vacuo. The crude product is purified using flashcolumn chromatography (20% ethyl acetate/hexanes) to afford 0.13 g (85%)desired{4-[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-ylmethoxy]-2-propyl-phenoxy}-aceticacid methyl ester. This ester is hydrolyzed in the usual way using 0.14g ester and 3 eq. 1M LiOH in 3 mL 3:2:1 THF:MeOH:H₂O to afford 0.16 g(95%) of the title compound.

Example 75{2-Methyl-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-ylmethanesulfonyl]-phenoxy}-aceticacid

To a suspension of5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-oxazole (0.30 g,1.8 mmol) and Cs₂CO₃ in 8 mL acetonitrile is added(4-Mercapto-2-methyl-phenoxy)-acetic acid ethyl ester (0.25 g, 1.1mmol). The solution is stirred for 6 hrs and poured into water (50 mL)and extracted with ethyl acetate (3×25 mL). The combined organics arewashed with water (10 mL) and brine (30 mL), dried (Na₂SO₄), filteredand concentrated in vacuo. The crude product is purified using flashcolumn chromatography (10%-20% ethyl acetate/hexanes) to afford 0.40 g(79%) of{2-Methyl-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-ylmethylsulfanyl]-phenoxy}-aceticacid ethyl ester. To a stirred solution of this ester (0.21 g, 0.44mmol) is added m-CPBA (50%) (0.31 g, 0.89 mmol) at 0° C. After 10 min.the solution is poured into water (50 mL) and extracted with methylenechloride (3×20 mL). The combine methylene chloride layers are washedwith 1 N NaOH (25 mL), water (25 mL) and brine (25 mL), dried (Na₂SO₄),filtered and concentrated in Vacuo. The crude sulphone is purified usingflash column chromatography (10%-25% ethyl acetate hexanes) to give 0.15g (68%) of{2-Methyl-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-ylmethanesulfonyl]-phenoxy}-aceticacid ethyl ester. Hydrolysis of this sulphone (0.15 g, 0.30 mmol)occurred under the usual conditions (3 eq. of a 1N solution of LiOH in 1mL of a 3:2:1 solution of THF:MeOH:H₂O) to provide the title compound0.11 g (78%) after workup with aq. NH₄Cl and ethyl acetate.

Example 76(4-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-aceticacid

MS M⁺+1 448. The structure is confirmed by ¹H NMR spectroscopy.

Example 77(3-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-phenyl)-aceticacid

MS M⁺+1 434. The structure is confirmed by ¹H NMR spectroscopy.

Example 78{3-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-ylmethoxy]-phenyl}-aceticacid

MS M⁺+1 420. The structure is confirmed by ¹H NMR spectroscopy.

Example 79{3-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-ylmethylsulfanyl]-phenyl}-aceticacid

MS M⁺+1 436. The structure is confirmed by ¹H NMR spectroscopy.

Example 80(3-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethylsulfanyl}-phenyl)-aceticacid

MS M⁺+1 450. The structure is confirmed by ¹H NMR spectroscopy.

Example 81{3-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-aceticacid

MS (ES): 436.2 (M⁺+1).

Example 82{3-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-aceticacid

MS (ES): 392.2 (M⁺+1).

Example 833-(2-Methyl-4-{[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethyl]-carbamoyl}-phenyl)-propionicacid

Step A3-(2-Methyl-4-{[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethyl]-carbamoyl}-phenyl)-propionicacid ethyl ester

To a mixture ofC-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-methylamine (0.2g, 0.78 mmol) and 4-(2-carboxy-ethyl)-3-methyl-benzoic acid (0.173 g,0.78 mmol) and DMAP (5 mg) in methylene chloride (5 mL) are addedtriethyl amin (0.12 mL, 0.86 mml) and EDCI (150 mg, 0.78 mmol) at roomtemperature. After stirred for 3 hrs, diluted with chloroform, washedwith water, 1N HCl and 2 N NaOH aqueous. Concentration and columnchromatography on silica gel gave the title compound (240 mg).

Step B3-(2-Methyl-4-{[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethyl]-carbamoyl}-phenyl)-propionicacid

To a solution of3-(2-methyl-4-{[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethyl]-carbamoyl}-phenyl)-propionicacid ethyl ester (70 mg) in enthanol (1 mL) is added NaOH (5.0 N, 1.0mL), the mixture is heated at 50° C. for 2 hrs, acidified with 5 N HCl,extracted with ethyl acetate, dried over sodium sulfate. Concentrationgave the title compound (70 mg).

Example 843-(4-{[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-amino}-2-methyl-phenyl)-propionicacid

Step A3-(4-{[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-amino}-2-methyl-phenyl)-propionicacid methyl ester

To a mixture of4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid(0.11 g, 0.35 mmol), 3-(4-Amino-2-methyl-phenyl)-propionic acid methylester (0.07 g, 0.35 mmol), and DMAP (0.01 g, 0.082 mmol) in CH₂Cl₂ (5mL) is added EDCI (0.08 g, 0.42 mmol). After stirring for 2 h at RT, themixture is concentrated. The residue is redissolved in EtOAc, and theorganics are washed with 1N HCl (1×), 2N NaOH (2×), water, and brine,and dried with MgSO₄. The crude material is purified by flashchromatography to yield the title compound (0.12 g, 70%).

Step B3-(4-{[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-amino}-2-methyl-phenyl)-propionicacid

Hydrolysis of the product from step one in the presence of sodiumhydroxide gave the title compound (32 mg, 55%). MS (ES): 477 (M⁺+1); thestructure is also confirmed by ¹H NMR.

The following compounds are made in a similar manner:

Example 853-(4-{2-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-acetylamino}-2-methyl-phenyl)-propionicacid

MS (ES): 477 (M⁺+1); the structure is also confirmed by ¹H NMR.

Example 863-[4-({[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-methyl-amino}-methyl)-2-methyl-phenyl]-propionicacid

(26 mg, 74%). MS (ES): 505 (M⁺); the structure is also confirmed by ¹HNMR.

Example 873-[4-({[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-amino}-methyl)-2-methyl-phenyl]-propionicacid

(37 mg, 62%). MS (ES): 491 (M⁺); the structure is also confirmed by ¹HNMR.

Example 88(2-Methyl-4-{[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethyl]-sulfamoyl}-phenoxy)-aceticacid

MS (ES): 485 (M⁺+1); the structure is also confirmed by ¹H NMR.

Example 893-(2-Methyl-4-{[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-phenyl)-propionicacid sodium salt

Step A3-(2-Methyl-4-{[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-phenyl)-propionicacid methyl ester

To a solution of 3-(4-Amino-2-methyl-phenyl)-propionic acid methyl ester(0.14 g, 0.70 mmol) and4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbaldehyde (0.19 g,0.71 mmol) in anhydrous CH₂Cl₂ (5 mL) is added 4 Å molecular sievesfollowed by acetic acid (50 μL, 0.87 mmol). The mixture is stirred at RTfor 2 h. Sodium triacetoxyborohydride (0.22 g, 1.04 mmol) is added, andthe mixture is stirred at RT for 12 h. The reaction is quenched withsaturated NaHCO₃. The organics are separated and washed with saturatedNaHCO₃ and brine, and dried with MgSO₄. The crude material is purifiedby flash chromatography to yield the title compound (0.21 g, 68%).

Step B3-(2-Methyl-4-{[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-phenyl)-Propionicacid sodium salt

A solution of3-(2-Methyl-4-{[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-phenyl)-propionicacid methyl ester (0.06 g, 0.13 mmol) and 5M NaOH (0.35 mL, 1.75 mmol)is heated to 70° C. for 14 h. Upon cooling, the solid is filtered anddried in vacuo to yield the title compound (10 mg, 17%) as the sodiumsalt. MS (ES): 435 (M⁺); the structure is also confirmed by ¹H NMR.

The following compounds are made in a similar manner:

Example 903-[4-({Bis-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-methyl)-2-methyl-phenyl]-propionicacid TFA salt

MS (ES): 704 (M⁺+1); the structure is also confirmed by ¹H NMR.

Example 913-[2-Methyl-4-({methyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-methyl)-phenyl]-propionicacid methyl ester TFA salt

MS (ES): 477 (M⁺+1); the structure is also confirmed by ¹H NMR.

Example 923-(4-{Methoxycarbonyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-2-methyl-phenyl)-propionicacid

Step A3-(4-{Methoxycarbonyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-2-methyl-phenyl)-propionicacid methyl ester

To a 0° C. solution of3-(2-Methyl-4-{[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-phenyl)-propionicacid methyl ester (0.05 g, 0.11 mmol) and pyridine (0.027 mL, 0.33 mmol)in anhydrous CH₂Cl₂ (3 mL) is added methyl chloroformate (0.026 mL, 0.34mmol) dropwise. The mixture is allowed to warm to RT overnight. Water isadded, and the mixture is extracted with CH₂Cl₂. The combined organicsare dried with MgSO₄ and concentrated to yield the title compound (57mg, quant.)

Step B3-(4-{Methoxycarbonyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-2-methyl-phenyl)-propionicacid

A similar procedure is followed to yield the title compound (0.048 g,81%). MS (ES): 493 (M⁺); the structure is also confirmed by ¹H NMR.

Example 933-{2-Methyl-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxymethyl]-phenyl}-propionicacid

Step A 5-Iodomethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole

To a solution of5-Chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole (0.51 g,1.73 mmol) in acetone is added NaI (0.42 g, 2.80 mmol). The mixture isstirred at RT for 3 h. The solid is filtered, and the filtrate isconcentrated. The resulting solid is washed with Et₂O and refiltered.Concentration of the filtrate yielded the title compound (0.68 g,quant.). The material is used without further purification.

Step B3-{2-Methyl-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxymethyl]-phenyl}-propionicacid methyl ester

To a solution of5-Iodomethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole (0.14 g,0.37 mmol) and 3-(4-Hydroxymethyl-2-methyl-phenyl)-propionic acid methylester (0.064 g, 0.31 mmol) in DMF (1 mL) is added sodium hydride (60%dispersion, 0.036 g, 1.50 mmol). The mixture is stirred at RT for 3 h.The reaction is quenched with water, and the mixture is extracted withEtOAc. The organics are dried with MgSO₄ and concentrated. The crudematerial is purified by flash chromatography to yield the title compound(0.022 g, 16%).

Step C3-{2-Methyl-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxymethyl]-phenyl}-propionicacid

A similar procedure is followed to yield the title compound (15 mg,73%). MS (ES): 450 (M⁺+1 the structure is also confirmed by ¹H NMR.

Example 943-{4-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxymethyl]-2-methyl-phenyl}-propionicacid

Step A3-{4-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxymethyl]-2-methyl-phenyl}-propionicacid methyl ester

To a mixture of[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol (0.056g, 0.18 mmol) and 3-(4-Iodomethyl-2-methyl-phenyl)-propionic acid methylester (0.070 g, 0.22 mol) in DMF (1 mL) is added sodium hydride (60%dispersion, 0.016 g, 0.67 mmol). After 3.5 h, water is added, and themixture is extracted with EtOAc. The organics are dried with MgSO₄ andconcentrated. The crude material is purified by flash chromatography toyield the title compound (55 mg, 60%).

Step B3-{4-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxymethyl]-2-methyl-phenyl}-propionicacid

A similar procedure is followed to yield the title compound (45 mg,84%). MS (ES) 478 (M⁺+1). The structure is also confirmed by ¹H NMR.

Example 953-[4-(2-{2-[6-(2-Fluoro-phenyl)-pyridin-3-yl]-5-methyl-thiazol-4-yl}-ethoxy)-2-methyl-phenyl]-propionicacid

Step A 6-(2-Fluoro-phenyl)-nicotinonitrile

A mixture of 6-Chloro-nicotinonitrile (7.26 g, 52.4 mmol) and2-fluorophenyl boronic acid (11 g, 78.6 mmol) and Na2CO3 (11 g, 103mmol) in toluene (200 mL) and water (10 mL) is degassed and filled withnitrogen for three times, then Pd(PPh3)4 (0.73 g) is added undernitrogen. The reaction mixture is heated at 90° C. After 12 hrs, thereaction mixture is cooled to room temperature, diluted with ethylacetate, washed with water, dried, concentrated. Column chromatographyon silica gel (Hexane/ethyl acetate as eluent) gave 9.8 g of6-(2-Fluoro-phenyl)-nicotinonitrile.

Step B 6-(2-Fluoro-phenyl)-thionicotinamide

A mixture of 6-(2-Fluoro-phenyl)-nicotinonitrile (9.8 g, 49.4 mmol) andthioacetamide (5.94 g, 79.1 mmol) in 4.0 M HCl in dioxane (200 mL) isheated at 100° C. for 3 days, cooled to room temperature. The ractionmixture is poured into old saturated sodium bicarbonate and stirred for30 min. Solid product is collected by filtration and dried under vacuumgiving the title compound (11.4 g).

Step C{2-[6-(2-Fluoro-phenyl)-pyridin-3-yl]-5-methyl-thiazol-4-yl}-acetic acidethyl ester

A mixture of 6-(2-Fluoro-phenyl)-thionicotinamide (1.5 g, 6 mmol) and4-Bromo-3-oxo-pentanoic acid methyl ester (1.51 g, 7.2 mmol) in ethanol(100 mL) is heated to reflux for 24 h, and concentrated. The residue ispurified by column chromatography on silica gel yielding 1.7 g of theproduct.

Step D2-{2-[6-(2-Fluoro-phenyl)-pyridin-3-yl]-5-methyl-thiazol-4-yl}-ethanol

To a solution of{2-[6-(2-Fluoro-phenyl)-pyridin-3-yl]-5-methyl-thiazol-4-yl}-acetic acidethyl ester (1.7 g, 4.77 mmol) in THF (10 mL) is added LiAlH4 (1.0 M inTHF, 4.8 mL, 4.8 mmol) at 0-5° C., and then stirred for 2 h. Thereaction is then quenched by water and 5 N NaOH, diluted with THF andfiltered through a pad of celite. The filtrate is concentrated andpurified by column yielding 1.4 g of the product.

Step E3-[4-(2-{2-[6-(2-Fluoro-phenyl)-pyridin-3-yl]-5-methyl-thiazol-4-yl}-ethoxy)-2-methyl-phenyl]-propionicacid tert-butyl ester

A solution of 3-(4-Hydroxy-2-methyl-phenyl)-propionic acid tert-butylester (120 mg, 0.5 mmol) and2-{2-[6-(2-Fluoro-phenyl)-pyridin-3-yl]-5-methyl-thiazol-4-yl}-ethanol(101 mg, 0.323 mmol) in toluene (3.0 mL) is degassed and filled withnitrogen for 3 times. Tributylphosphine (0.124 mL, 0.5 mmol) is added tothe reaction mixture under nitrogen at 0° C., followed by addition of of1,1′-(azodicarbonyl)-dipiperidine (120 mg, 0.5 mmol). The reactionmixture is allowed to warm to room temperature and stirred overnight,the mixture is loaded on silica gel column. Chromatography gave thetitle compound (130 mg).

Step F3-[4-(2-{2-[6-(2-Fluoro-phenyl)-pyridin-3-yl]-5-methyl-thiazol-4-yl}-ethoxy)-2-methyl-phenyl]-propionicacid

To a solution of3-[4-(2-{2-[6-(2-Fluoro-phenyl)-pyridin-3-yl]-5-methyl-thiazol-4-yl}-ethoxy)-2-methyl-phenyl]-propionicacid tert-butyl ester (130 mg) in methylene chloride (1 mL) is added TFA(0.8 mL) and two drops of water. The mixture is stirred for 2 h, andconcentrated and purified by reversed phase HPLC (water-acetonitrilewith 0.1% TFA) yield 120 mg of product. MS (ES): 477.2(M⁺+1).

The following compounds are made in substantially similar method:

Example 963-[4-(2-{2-[6-(3-Fluoro-phenyl)-pyridin-3-yl]-5-methyl-thiazol-4-yl}-ethoxy)-2-methyl-phenyl]-propionicacid

MS (ES): 477.2 (M⁺+1).

Example 973-[4-(2-{2-[6-(4-Fluoro-phenyl)-pyridin-3-yl]-5-methyl-thiazol-4-yl}-ethoxy)-2-methyl-phenyl]-propionicacid

MS (ES): 477.2(M⁺+1).

Example 983-[4-(2-{2-[6-phenyl-pyridin-3-yl]-5-methyl-thiazol-4-yl}-ethoxy)-2-methyl-phenyl]-propionicacid

MS (ES): 459.1(M⁺+1).

Example 993-[4-(2-{2-[6-(2-methyl-phenyl)-pyridin-3-yl]-5-methyl-thiazol-4-yl}-ethoxy)-2-methyl-phenyl]-propionicacid

MS (ES): 473.5(M⁺+1).

Example 1003-[4-(2-{2-[6-(3-methyl-phenyl)-pyridin-3-yl]-5-methyl-thiazol-4-yl}-ethoxy)-2-methyl-phenyl]-propionicacid

MS (ES): 473.5(M⁺+1).

Example 1013-[4-(2-{2-[6-(4-methyl-phenyl)-pyridin-3-yl]-5-methyl-thiazol-4-yl}-ethoxy)-2-methyl-phenyl]-propionicacid

MS (ES): 473.4(M⁺+1).

Example 1023-{4-[2-(2-[2,2′]Bipyridinyl-5-yl-5-methyl-thiazol-4-yl)-ethoxy]-2-methyl-phenyl}-propionicacid

MS (ES): 460.5 (M⁺+1)

Example 1033-(2-Methyl-4-{2-[5-methyl-2-(6-phenoxy-pyridin-3-yl)-thiazol-4-yl]-ethoxy}-phenyl)-propionicacid

MS (ES): 475.4 (M⁺+1).

Example 1043-(2-Methyl-4-{2-[5-methyl-2-(6-phenoxy-pyridin-3-yl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid, HCl salt

MS (ES): 459.2(M⁺+1-HCl)

Example 1053-(2-Methyl-4-{2-[5-methyl-2-(6-phenylsulfanyl-pyridin-3-yl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid, HCl salt

MS (ES): 475.1(M⁺+1-HCl).

Example 1063-(2-Methyl-4-{2-[5-methyl-2-(6-phenyl-pyridin-3-yl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid

Step A 6-chloro-nicotinic acid 3-methoxycarbonyl-1-methyl-2-oxo-propylester

To a solution of 6-Chloro-nicotinic acid (10 g, 63.5 mmol) and4-Bromo-3-oxo-pentanoic acid methyl ester (1.51 g, 7.2 mmol) (14.6 g, 70mmol) in acetone (100 mL) is added triethyl amine (9.76 mL, 70 mmol) at0-5° C. After addition, the reaction mixture is warmed to roomtemperature and stirred overnight, solid is filtered off, the filtrateis concentrated and taken into methylene chloride, washed with water andbrine, dried. The residue is purified by column giving6-chloro-nicotinic acid 3-methoxycarbonyl-1-methyl-2-oxo-propyl ester(16.3 g.

Step B [2-(6-Chloro-pyridin-3-yl)-5-methyl-oxazol-4-yl]-acetic acidmethyl ester

A mixture of 6-chloro-nicotinic acid3-methoxycarbonyl-1-methyl-2-oxo-propyl ester (16.3 g, 57.1 mmol) andammonium acetate (18.5 g, 240 mmol) in ethanol (150 mL) is heated at 80°C. for 2 h, concentrated. The residue is taken into acetic acid (330 mL)and heated to reflux overnight, concentrated. The residue is taken intoethyl acetate and washed with water, dried, concentrated, purified bycolumn giving [2-(6-Chloro-pyridin-3-yl)-5-methyl-oxazol-4-yl]-aceticacid methyl ester (4.3 g).

Step C 2-[2-(6-Chloro-pyridin-3-yl)-5-methyl-oxazol-4-yl]-ethanol

To a solution of [2-(6-Chloro-pyridin-3-yl)-5-methyl-oxazol-4-yl]-aceticacid methyl ester (4.0 g, 15 mmol) from step B in THF (50 mL) is added asolution of lithium aluminum hydride in THF (1.0 M, 12.5 mL, 12.5 mmol)at 0° C. After 1 hr, the reaction is quenched by water and sodiumhydroxide, filtered, concentrated. The crude material is used for thenext step.

Step D Toluene-4-sulfonic acid2-[2-(6-chloro-pyridin-3-yl)-5-methyl-oxazol-4-yl]-ethyl ester

The crude 2-[2-(6-Chloro-pyridin-3-yl)-5-methyl-oxazol-4-yl]-ethanolfrom step C is dissolved in methylene chloride (50 mL), then TsCl, DMAPand triethyl amine are added and stirred overnight. The reaction mixtureis washed with water, brine and concentrated. Column chromatography onsilica gel gave the title compound (0.5 g).

Step E3-(4-{2-[2-(6-Chloro-pyridin-3-yl)-5-methyl-oxazol-4-yl]-ethoxy}-2-methyl-phenyl)-propionicacid methyl ester

A mixture of toluene-4-sulfonic acid2-[2-(6-chloro-pyridin-3-yl)-5-methyl-oxazol-4-yl]-ethyl ester (0.4 g,1.0 mmol, 3-(4-Hydroxy-2-methyl-phenyl)-propionic acid methyl ester (0.2g, 1 mmol) and Cs2CO3 (0.49 g, 1.5 mmol) in DMF (5 mL) is heated at 60°C. overnight, cooled to room temperature, diluted with ethyl acetate,washed with water and dried. Column chromatography on silica gel gavethe product (85 mg).

Step F3-(2-Methyl-4-{2-[5-methyl-2-(6-phenyl-pyridin-3-yl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid methyl ester

A mixture of3-(4-{2-[2-(6-Chloro-pyridin-3-yl)-5-methyl-oxazol-4-yl]-ethoxy}-2-methyl-phenyl)-propionicacid methyl ester (41 mg, 0.1 mmol) and phenyl boronic acid (25 mg, 0.2mmol) and Na2CO3 (22 mg, 0.2 mmol) in toluene (0.5 mL) and water (0.1mL) is degassed and filled with nitrogen for three times, then Pd(PPh3)4(3 mg) is added under nitrogen. The reaction mixture is heated at 90° C.After 12 hrs, the reaction mixture is cooled to room temperature,diluted with ethyl acetate, washed with water, dried, concentrated.Column chromatography on silica gel (Hexane/ethyl acetate as eluent)gave 45 mg of product.

Step G3-(2-Methyl-4-{2-[5-methyl-2-(6-phenyl-pyridin-3-yl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid

To a solution of3-(2-Methyl-4-{2-[5-methyl-2-(6-phenyl-pyridin-3-yl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid methyl ester (40 mg) in ethanol (1 mL) is added NaOH (5 N, 1.0 mL),stirred for 2 hr at 50° C., cooled to room temperature, concentrated.The residue is treated with ether and acidified by 5 N HCl, extractedwith ether, concentrated. Reversed phase HPLC (water/acetonitrile) gavethe title compound (22 mg). MS (ES): 443.3 (M⁺+1).

The following compound is made in a substantially similar method:

Example 1073-[4-(2-{2-[6-(2-Fluoro-phenyl)-pyridin-3-yl]-5-methyl-oxazol-4-yl}-ethoxy)-2-methyl-phenyl]-propionicacid

MS (ES): 461.4 (M⁺+1).

Example 1083-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-2-yl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionicacid

Step A

3-(4-{2-[2-(4-Bromo-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-2-methyl-phenyl)-propionicacid (100 mg, 0.21 mmol) is dissolved in anhydrous toluene (1 mL),degassed, and filled with nitrogen three times. Palladium tetrakistriphenyl phosphine [Pd(PPh₃)₄, 21 mg, 0.0021 mmol] is added, and thedegassing procedure is repeated. 2-tributylstannylpyridine (63 uL, 0.25mmol) is then added via syringe and the reaction is heated to reflux.The reaction is monitored by HPLC. Upon complete consumption of startingmaterial, the reaction is allowed to cool to room temperature anddiluted with ethyl acetate. Celite is added and the mixture is filteredand rinsed with more ethyl acetate and water. The solution is furtherdiluted with water and the two phases are separated. The organic layeris washed with water and brine, dried over anhydrous sodium sulfate,filtered, and concentrated. The pure3-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-2-yl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionicacid methyl ester is obtained after column chromatography.

Step B3-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-2-yl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionicacid

methyl ester from step A is dissolved in tetrahydrofuran (1 mL) and 5Nsodium hydroxide (1 mL) solution is added with stirring at roomtemperature. The reaction is heated to reflux and monitored by HPLC.Upon complete conversion, the reaction is allowed to cool to roomtemperature and neutralized with 5N hydrochloric acid (1 mL), dilutedwith ethyl acetate, and extracted. The organic layer is washed withwater and brine, dried over anhydrous sodium sulfate, filtered, andconcentrated. The pure3-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-2-yl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionicacid (46 mg) may also be obtained by recrystalization from ethyl acetate(48% yield 2 steps), MS (ES): 459.2 (M⁺+1).

The following compounds are made in a similar manner:

Example 1093-(2-Methyl-4-{2-[5-methyl-2-(4-pyrimidin-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid

MS (ES): 444.2 (M⁺+1).

Example 1103-{4-[2-(2-[2,2′]Bipyridinyl-5-yl-5-methyl-oxazol-4-yl)-ethoxy]-2-methyl-phenyl}-propionicacid, bis HCl salt

This compound is made in a similar method starting from6-chloro-nicotinic acid. MS (ES): 444.2 (M⁺−2 HCl+1).

Example 1113-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid

Step A3-[2-Methyl-4-(2-{5-methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazol-4-yl}-ethoxy)-phenyl]-propionicacid methyl ester

3-(4-{2-[2-(4-Bromo-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-2-methyl-phenyl)-propionicacid methyl ester (2.0 g, 4.36 mmol) is dissolved in anhydrous methylsulfoxide (25 mL), degassed, and filled with nitrogen three times.[1,1′-Bis-(diphenylphosphino)ferrocene] dichloropalladium(II) (50 mg)bis(pinacolato)diboron (1.66 g, 6.54 mmol), and potassium acetate (1.71g, 17.4 mmol) are added, and the degassing procedure is repeated. Thereaction is heated to 85° C. and monitored by HPLC. Upon completeconsumption of starting material, the reaction is allowed to cool toroom temperature and diluted with ethyl acetate. Celite is added and themixture is filtered and rinsed with more ethyl acetate and water. Thesolution is further diluted with water and the two phases are separated.The organic layer is washed with water and brine, dried over anhydroussodium sulfate, filtered, and concentrated. The pure3-[2-Methyl-4-(2-{5-methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazol-4-yl}-ethoxy)-phenyl]-propionicacid methyl ester (0.9 g) is obtained after column chromatography.

Step B3-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid methyl ester

3-[2-Methyl-4-(2-{5-methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazol-4-yl}-ethoxy)-phenyl]-propionicacid methyl ester (167 mg; 0.328 mmol) is dissolved in anhydrous toluene(1 mL), degassed, and filled with nitrogen three times.[1,1′-Bis-(diphenylphosphino)ferrocene]dichloropalladium(II) (15 mg,0.02 mmol), 2-bromopyridine (67 ul, 0.7 mmol), and sodium carbonate (150uL, 10 M aqueous, 1.5 mmol) are added, and the degassing procedure isrepeated. The reaction is heated to 100° C. and monitored by HPLC. Uponcomplete consumption of starting material, the reaction is allowed tocool to room temperature and diluted with ethyl acetate. Celite is addedand the mixture is filtered and rinsed with more ethyl acetate andwater. The solution is further diluted with water and the two phases areseparated. The organic layer is washed with water and brine, dried overanhydrous sodium sulfate, filtered, and concentrated.

Step C

3-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid methyl ester from step B is dissolved in tetrahydrofuran (1 mL) and5N sodium hydroxide (1 mL) solution is added with stirring at roomtemperature. The reaction is heated to reflux and monitored by HPLC.Upon complete conversion, the reaction is allowed to cool to roomtemperature and neutralized with 5N hydrochloric acid (1 mL), dilutedwith ethyl acetate, and extracted. The organic layer is washed withwater and brine, dried over anhydrous sodium sulfate, filtered, andconcentrated. The pure3-(2-methyl-4-{2-[5-methyl-2-(4-pyridin-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid (58 mg, 0.13 mmol, 40% yield for two steps) may also be obtained byrecrystalization from ethyl acetate, MS (ES): 443.2 (M⁺+1).

The following compounds are made in a similar manner:

Example 1123-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-4-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid

MS (ES): 443.2 (M⁺+1).

Example 1133-[2-Methyl-4-(2-{5-methyl-2-[4-(5-methyl-pyridin-2-yl)-phenyl]-oxazol-4-yl}-ethoxy)-phenyl]-propionicacid, trifluoroacetic acid salt

MS (ES): 457.2 (M⁺+1-TFA).

Example 1143-[2-Methyl-4-(2-{5-methyl-2-[4-(6-methyl-pyridin-2-yl)-phenyl]-oxazol-4-yl}-ethoxy)-phenyl]-propionicacid, trifluoroacetic acid salt

MS (ES): 457.2 (M⁺+1-TFA).

Example 1153-[2-Methyl-4-(2-{5-methyl-2-[4-(3-methyl-pyridin-2-yl)-phenyl]-oxazol-4-yl}-ethoxy)-phenyl]-propionicacid

MS (ES): 457.3 (M⁺+1)

Example 1163-(2-Methyl-4-{2-[5-methyl-2-(4-pyrimidin-4-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid

MS (ES): 444.2 (M⁺+1).

Example 1173-(2-Methyl-4-{3-[5-methyl-2-(4-pyridin-2-yl-phenyl)-oxazol-4-yl]-propoxy}-phenyl)-propionicacid, HCl salt

MS (ES): 457.4 (M⁺+1-HCl).

Example 1183-[2-Methyl-4-(2-{5-methyl-2-[3-(5-methyl-pyridin-2-yl)-phenyl]-oxazol-4-yl}-ethoxy)-phenyl]-propionicacid, trifluoroacetic acid salt

MS (ES): 457.2 (M⁺+1-TFA).

Example 1193-[2-Methyl-4-(2-{5-methyl-2-[3-(6-methyl-pyridin-2-yl)-phenyl]-oxazol-4-yl}-ethoxy)-phenyl]-propionicacid, trifluoroacetic acid salt

MS (ES): 457.2 (M⁺+1-TFA).

Example 1203-[2-Methyl-4-(2-{5-methyl-2-[3-pyridin-2-yl-phenyl]-oxazol-4-yl}-ethoxy)-phenyl]-propionicacid, trifluoroacetic acid salt

MS (ES): 443.2 (M⁺+1-TFA).

Example 1213-(2-Methyl-4-{2-[5-methyl-2-(3-pyrimidin-4-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid

MS (ES): 444.2 (M⁺+1).

Example 1223-(2-Methyl-4-{2-[5-methyl-2-(3-pyrimidin-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid

MS (ES): 444.2 (M⁺+1).

Example 1233-(2-Methyl-4-{2-[5-methyl-2-(4-pyrimidin-2-yl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionicacid

MS (ES) 460.0 (M⁺+1).

Example 1243-(2-Methyl-4-{2-[5-methyl-2-(4-pyrazin-2-yl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionicacid

MS (ES): 460.2 (M⁺+1).

Example 1253-(2-Methyl-4-{2-[5-methyl-2-(4-pyrazin-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid

MS (ES): 444.2 (M⁺+1).

Example 1263-(2-Methyl-4-{2-[5-methyl-2-(3-pyrazin-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid

MS (ES): 444.2 (M⁺+1).

Example 1273-[2-Methyl-4-(2-{5-methyl-2-[4-(6-methyl-pyridazin-3-yl)-phenyl]-oxazol-4-yl}-ethoxy)-phenyl]-propionicacid

MS (ES): 458.2 (M⁺+1).

Example 1283-(2-Methyl-4-{2-[5-methyl-2-(3-pyrazin-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid

MS (ES): 458.2 (M⁺+1).

Example 1293-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-3-yl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionicacid

Step A

3-(4-{2-[2-(4-Bromo-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-2-methyl-phenyl)-propionicacid methyl ester (100 mg, 0.200 mmol) is dissolved in toluene (1 mL),degassed, and filled with nitrogen three times. Palladiumtetrakistriphenyl phosphine (10 mg, 0.010 mmol), 3-pyridylboronic acid(31 mg, 0.250 mmol), and sodium carbonate (100 uL of a 10M solution,0.400 mmol) are added, and the degassing procedure is repeated. Ethanol(1 mL) is added to dissolve the boronic acid. The reaction is heated to100° C. and monitored by HPLC. Upon complete consumption of startingmaterial, the reaction is allowed to cool to room temperature anddiluted with ethyl acetate. Celite is added and the mixture is filteredand rinsed with more ethyl acetate and water. The solution is furtherdiluted with water and the two phases are separated. The organic layeris washed with water and brine, dried over anhydrous sodium sulfate,filtered, and concentrated. The pure3-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-3-yl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionicacid methyl ester (47 mg, 0.100 mmol) is obtained after columnchromatography (50% yield).

Step B

3-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-3-yl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionicacid methyl ester (47 mg, 0.100 mmol) is dissolved in tetrahydrofuran (1mL) and 5N sodium hydroxide (1 mL) solution is added at roomtemperature. The reaction is heated to reflux and monitored by HPLC.Upon complete conversion, the reaction is allowed to cool to roomtemperature and neutralized with 5N hydrochloric acid (1 mL), dilutedwith ethyl acetate, and extracted. The organic layer is washed withwater and brine, dried over anhydrous sodium sulfate, filtered, andconcentrated. The pure3-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-3-yl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionicacid (40 mg, 0.087 mmol) may also be obtained by recrystalization fromethyl acetate (87% yield). MS (ES): 459.2 (M⁺+1). Alternatively, theacid may be obtained after reversed phase preparative HPLC as thehydrochloride salt.

The following compounds are made in a similar manner:

Example 1303-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-4-yl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionicacid

MS (ES): 459.2 (M⁺+1).

Example 1313-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-3-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid

MS (ES): 443.2 (M⁺+1).

Example 1323-(2-Methyl-4-{2-[5-methyl-2-(3-pyridin-3-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid

MS (ES): 443.2 (M⁺+1).

Example 1333-(2-Methyl-4-{2-[5-methyl-2-(3-pyridin-4-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid

MS (ES): 443.2 (M⁺+1).

Biological Assays

Binding and Cotransfection Studies

The in vitro potency of compounds in modulating PPAR receptors aredetermined by the procedures detailed below. DNA-dependent binding (ABCDbinding) is carried out using SPA technology with PPAR receptors.Tritium-labeled PPAR selective agonists are used as radioligands forgenerating displacement curves and IC₅₀ values with compounds of theinvention. Cotransfection assays are carried out in CV-1 cells. Thereporter plasmid contained an acylCoA oxidase (AOX) PPRE and TK promoterupstream of the luciferase reporter cDNA. Appropriate PPARs areconstitutively expressed using plasmids containing the CMV promoter. ForPPARα, interference by endogenous PPARγ in CV-1 cells is an issue. Inorder to eliminate such interference, a GAL4 chimeric system is used inwhich the DNA binding domain of the transfected PPAR is replaced by thatof GAL4, and the GAL4 response element is utilized in place of the AOXPPRE. Cotransfection efficacy is determined relative to PPARα agonistreference molecules. Efficacies are determined by computer fit to aconcentration-response curve, or in some cases at a single highconcentration of agonist (10 μM). These studies are carried out toevaluate the ability of compounds of the invention to bind to and/oractivate various nuclear transcription factors, particularly huPPARα(“hu” indicates “human”). These studies provide in vitro data concerningefficacy and selectivity of compounds of the invention. Furthermore,binding and cotransfection data for compounds of the invention arecompared with corresponding data for marketed compounds that act onhuPPARα. The binding and cotransfection efficacy values found, forcompounds of the invention and compounds of this invention which areuseful for modulating a PPAR alpha receptor, are ≦100 nM and ≧50%,respectively.

Binding Assay:

DNA-dependent binding is carried out using Scintillation Proximity Assay(SPA) technology (Amersham Pharmacia Biotech). PPARγ, PPARα and PPARδreceptors as well as their heterodimer partner RXRα receptor areprepared using a baculovirus expression system. Biotinylatedoligonucleotide ^(5′)TAATGTAGGTAATAGTTCAATAGGTCAAAGGG^(3′) is used forbinding of receptor dimers to Yttrium silicate streptavidin-coated SPAbeads. PPARγ labeled ligand is ³H-reference, and PPARα and PPARδ•labeledligands is ³H-reference with specific activity of 52 Ci/mmol and 90Ci/mmol, respectively. Competition binding reactions are carried out in10 mM HEPES pH 7.8, 80 mM KCl, 0.5 mM MgCl₂, 1 mM DTT, 0.5% CHAPS, 14%glycerol, using 2.5 μg of each of PPARγ, α or δ and RXRα receptors, 5 nMto 10 μM of competing compounds and 30,000 cpm of corresponding labeledligand.

Co-transfection Assay:

Co-transfection assays are performed in CV-1 cells using calciumphosphate coprecipitation as previously described (Berger et al. SteroidBiochem. Mol. Biol. 41:733, 1992; Mukherjee et al. Nature 386:407-410,1997). The reporter plasmid contained an acylCoA oxidase (AOX) PPRE andTK promoter upstream of the luciferase reporter cDNA. PPARs and RXRα areconstitutively expressed using plasmids containing the CMV promoter. ForPPARα•or•δ, interference by endogenous PPARs in CV-1 cells is eliminatedby using a GAL4 chimeric system in which the DNA binding domain of thetransfected PPARαor•δ is replaced by that of GAL4, and the GAL4 responseelement is utilized in place of the AOX PPRE. CV-1 cells are transfectedin T225 cm² flasks in DMEM with 10% Fetal Bovine Serum (FBS). After anovernight incubation, transfected cells are trypsinized and plated in 96well dishes in DMEM media containing 10% charcoal-stripped FBS. After a6 h incubation, cells are exposed to 0.1 nM to 10 μM of test compounds.Co-transfection efficacy is determined using reference compounds.Compounds of this invention that are selective for the PPARδ are atleast 10-fold selective for PPAR•• over PPARα and PPARγ.

Evaluation of Triglyceride Reduction and HDL Cholesterol Elevation inHuapoAI Transgenic Mice

Seventeen different series of studies are performed to evaluate theeffect of compounds of the present invention upon HDL and triglyceridelevels in human apoAI mice. For each compound tested, seven to eightweek old male mice, transgenic for human apoAI (C57BL/6-tgn(apoa1)1rub,Jackson Laboratory, Bar Harbor, Me.) are acclimated in individual cagesfor two weeks with standard chow diet (Purina 5001) and water providedad libitum. After the acclimation, mice and chow are weighed andassigned to test groups (n=5) with randomization by body weight. Miceare dosed daily by oral gavage for 8 days using a 29 gauge, 1 1/2 inchcurved feeding needle (Popper & Sons). The vehicle for the controls,test compounds and the positive control (fenofibrate 100 mg/kg) is 1%carboxymethylcellulose (w/v) with 0.25% tween 80 (w/v). All mice aredosed daily between 6 and 8 a.m. with a dosing volume of 0.2 ml. Priorto termination, animals and diets are weighed and body weight change andfood consumption are calculated. Three hours after last dose, mice areeuthanized with CO₂ and blood is removed (0.5-1.0 ml) by cardiacpuncture. After sacrifice, the liver, heart, and epididymal fat pad areexcised and weighed. Blood is permitted to clot and serum is separatedfrom the blood by centrifugation.

Cholesterol and triglycerides are measured calorimetrically usingcommercially prepared reagents (for example, as available from Sigma#339-1000 and Roche #450061 for triglycerides and cholesterol,respectively). The procedures are modified from published work (McGowanM. W. et al., Clin Chem 29:538-542, 1983; Allain C. C. et al., Clin Chem20:470-475, 1974. Commercially available standards for triglycerides andtotal cholesterol, respectively, commercial quality control plasma, andsamples are measured in duplicate using 200 μl of reagent. An additionalaliquot of sample, added to a well containing 200 μl water, provided ablank for each specimen. Plates are incubated at room temperature on aplate shaker and absorbance is read at 500 nm and 540 nm for totalcholesterol and triglycerides, respectively. Values for the positivecontrol are always within the expected range and the coefficient ofvariation for samples is below 10%. All samples from an experiment areassayed at the same time to minimize inter-assay variability.

Serum lipoproteins are separated and cholesterol quantitated by fastprotein liquid chromatography (FPLC) coupled to an in line detectionsystem. Samples are applied to a Superose 6 HR size exclusion column(Amersham Pharmacia Biotech) and eluted with phosphate bufferedsaline-EDTA at 0.5 ml/min. Cholesterol reagent (for example, RocheDiagnostics Chol/HP 704036) at 0.16 ml/min mixed with the columneffluent through a T-connection and the mixture passed through a 15m×0.5 mm id knitted tubing reactor immersed in a 37 C water bath. Thecolored product produced in the presence of cholesterol is monitored inthe flow strem at 505 nm and the analog voltage from the monitor isconverted to a digital signal for collection and analysis. The change involtage corresponding to change in cholesterol concentration is plottedvs time and the area under the curve corresponding to the elution ofvery low density lipoprotein (VLDL), low density lipoprotein (LDL) andhigh density lipoprotein (HDL) is calculated using Perkin ElmerTurbochrome software.

Triglyceride Serum Levels in Mice Dosed with a Compound of the Inventionis compared to Mice Receiving the Vehicle to identify compounds thatcould be particularly useful for lowering triglycerides. Generally,triglyceride decreases of greater than or equal to 30% (thirty percent)compared to control following a 30 mg/kg dose suggests a compound thatcan be especially useful for lowering triglyceride levels.

The percent increase of HDLc serum levels in mice receiving a compoundof the invention is compared to mice receiving vehicle to identifycompounds of the invention that could be particularly useful forelevating HDL levels. Generally, and increase of greater than or equalto 25% (twenty five percent) increase in HDLc level following a 30 mg/kgdose suggests a compound that can be especially useful for elevatingHDLc levels.

It may be particularly desirable to select compounds of this inventionthat both lower triglyceride levels and increase HDLc levels. However,compounds that either lower triglyceride levels or increase HDLc levelsmay be desirable as well.

Evaluation of Glucose Levels in db/db Mice

The effects, upon plasma glucose of administering various dose levels offive different compounds of the present invention and the PPAR gammaagonist rosiglitazone or the PPAR alpha agonist fenofibrate, and thecontrol, to male db/db mice, are studied.

Five week old male diabetic (db/db) mice [for example, C57BlKs/j-m +/+Lepr(db), Jackson Laboratory, Bar Harbor, Me.] or lean littermates arehoused 6 per cage with food and water available at all times. After anacclimation period of 2 weeks, animals are individually identified byear notches, weighed, and bled via the tail vein for determination ofinitial glucose levels. Blood is collected (100 μl) from unfastedanimals by wrapping each mouse in a towel, cutting the tip of the tailwith a scalpel, and milking blood from the tail into a heparinizedcapillary tube. Sample is discharged into a heparinized microtainer withgel separator and retained on ice. Plasma is obtained aftercentrifugation at 4° C. and glucose measured immediately. Remainingplasma is frozen until the completion of the experiment, when glucoseand triglycerides are assayed in all samples. Animals are grouped basedon initial glucose levels and body weights. Beginning the followingmorning, mice are dosed daily by oral gavage for 7 days. Treatments aretest compounds (30 mg/kg), a positive control agent (30 mg/kg) orvehicle [1% carboxymethylcellulose (w/v)/0.25% Tween80 (w/v); 0.3ml/mouse]. On day 7, mice are weighed and bled (tail vein) 3 hours afterdosing. Twenty-four hours after the 7^(th) dose (i.e., day 8), animalsare bled again (tail vein). Samples obtained from conscious animals ondays 0, 7 and 8 are assayed for glucose. After the 24 hour bleed,animals are weighed and dosed for the final time. Three hours afterdosing on day 8, animals are anesthetized by inhalation of isofluraneand blood obtained via cardiac puncture (0.5-0.7 ml). Whole blood istransferred to serum separator tubes, chilled on ice and permitted toclot. Serum is obtained after centrifugation at 4° C. and frozen untilanalysis for compound levels. After sacrifice by cervical dislocation,the liver, heart and epididymal fat pads are excised and weighed.

Glucose is measured calorimetrically using commercially purchasedreagents. According to the manufacturers, the procedures are modifiedfrom published work (McGowan, M. W., Artiss, J. D., Strandbergh, D. R. &Zak, B. Clin Chem, 20:470-5 (1974) and Keston, A. Specific calorimetricenzymatic analytical reagents for glucose. Abstract of papers 129thMeeting ACS, 31C (1956).); and depend on the release of a mole ofhydrogen peroxide for each mole of analyte, coupled with a colorreaction first described by Trinder (Trinder, P. Determination ofglucose in blood using glucose oxidase with an alternative oxygenacceptor. Ann Clin Biochem, 6:24 (1969)). The absorbance of the dyeproduced is linearly related to the analyte in the sample. The assaysare further modified in our laboratory for use in a 96 well format. Thecommercially available standard for glucose, commercially availablequality control plasma, and samples (2 or 5 μl/well) are measured induplicate using 200 μl of reagent. An additional aliquot of sample,pipetted to a third well and diluted in 200 μl water, provided a blankfor each specimen. Plates are incubated at room temperature for 18minutes for glucose on a plate shaker (DPC Micormix 5) and absorbanceread at 500 nm on a plate reader. Sample absorbances are compared to astandard curve (100-800 for glucose). Values for the quality controlsample are always within the expected range and the coefficient ofvariation for samples is below 10%. All samples from an experiment areassayed at the same time to minimize inter-assay variability.

The results of the study, suggest compounds of the present inventionthat significantly reduced db/db mouse plasma glucose levels whileresulting in body weight gains that are generally less than thoseobserved for rosiglitazone.

Evaluation of the Effects of Compounds of the Present Invention uponA^(y) Mice Body Weight, Fat Mass, Glucose and Insulin Levels

Female A^(y) Mice

Female A^(y) mice are singly housed, maintained under standardizedconditions (22° C., 12 h light:dark cycle), and provided free access tofood and water throughout the duration of the study. At twenty weeks ofage the mice are randomly assigned to vehicle control and treated groupsbased on body weight and body fat content as assessed by DEXA scanning(N=6). Mice are then dosed via oral gavage with either vehicle or aCompound of this invention (50 mg/kg) one hour after the initiation ofthe light cycle (for example, about 7 A.M.) for 18 days. Body weightsare measured daily throughout the study. On day 14 mice are maintainedin individual metabolic chambers for indirect calorimetry assessment ofenergy expenditure and fuel utilization. On day 18 mice are againsubjected to DEXA scanning for post treatment measurement of bodycomposition.

The results of p.o. dosing of compound for 18 days on body weight, fatmass, and lean mass are evaluated and suggest which compounds of thisinvention can be especially useful for maintaining desirable weightand/or promoting desired lean to fat mass.

Indirect calorimetry measurements revealed a significant reduction inrespiratory quotient (RQ) in treated animals during the dark cycle[0.864±0.013 (Control) vs. 0.803±0.007 (Treated); p<0.001]. Thisreduction in RQ is indicative of an increased utilization of fat duringthe animals' active (dark) cycle. Additionally, treated animalsdisplayed significantly higher rates of energy expenditure than controlanimals (17.40±0.49 vs. 13.62±0.26 kcal/kg/hr, respectively).

Male KK/A^(y) Mice

Male KK/A^(y) mice are singly housed, maintained under standardizedconditions (22° C., 12 h light:dark cycle), and provided free access tofood and water throughout the duration of the study. At twenty-two weeksof age the mice are randomly assigned to vehicle control and treatedgroups based on plasma glucose levels. Mice are then dosed via oralgavage with either vehicle or a Compound of this invention (30 mg/kg)one hour after the initiation of the light cycle (7 A.M.) for 14 days.Plasma glucose, triglyceride, and insulin levels are assessed on day 14.

The results of p.o. dosing of compound for 14 days on plasma glucose,triglycerides, and insulin are evaluated to identify compounds of thisinvention that may be especially desired.

Method to Elucidate the LDL-cholesterol Total-cholesterol andTriglyceride Lowering Effect

Male Syrian hamsters (Harlan Sprague Dawley) weighing 80-120 g areplaced on a high-fat cholesterol-rich diet for two to three weeks priorto use. Feed and water are provided ad libitum throughout the course ofthe experiment. Under these conditions, hamsters becomehypercholesterolemic showing plasma cholesterol levels between 180-280mg/dl. (Hamsters fed with normal chow had a total plasma cholesterollevel between 100-150 mg/dl.) Hamsters with high plasma cholesterol (180mg/dl and above) are randomized into treatment groups based on theirtotal cholesterol level using the GroupOptimizeV211.xls program.

A Compound of this invention is dissolved in an aqueous vehicle(containing CMC with Tween 80) such that each hamster receives once aday approx. 1 ml of the solution by garvage at doses 3 and 30 mg/kg bodyweight. Fenofibrate (Sigma Chemical, prepared as a suspension in thesame vehicle) is given as a known alpha-agonist control at a dose of 200mg/kg, and the blank control is vehicle alone. Dosing is performed dailyin the early morning for 14 days.

Quantification of Plasma Lipids:

On the last day of the test, hamsters are bled (400 ul) from thesuborbital sinus while under isoflurane anesthesia 2 h after dosing.Blood samples are collected into heparinized microfuge tubes chilled inice bath. Plasma samples are separated from the blood cells by briefcentrifugation. Total cholesterol and triglycerides are determined bymeans of enzymatic assays carried out automatically in the Monarchequipment (Instrumentation Laboratory) following the manufacturer'sprecedure. Plasma lipoproteins (VLDL, LDL and HDL) are resolved byinjecting 25 ul of the pooled plasma samples into an FPLC system elutedwith phosphate buffered saline at 0.5 ml/min through a Superose 6 HR10/30 column (Pharmacia) maintained room temp. Detection andcharacterization of the isolated plasma lipids are accomplished bypostcolumn incubation of the effluent with a Cholesterol/HP reagent (forexample, Roche Lab System; infused at 0.12 ml/min) in a knitted reactioncoil maintained at 37° C. The intensity of the color formed isproportional to the cholesterol concentration and is measuredphotometrically at 505 nm.

The effect of administration of a Compound of this invention for 14 daysis studied for the percent reduction in LDL level with reference to thevehicle group. The LDL-lowering efficacy for certain compounds of thisinvention is markedly more potent than that of fenofibrate. Compounds ofthis invention that decrease LDL greater than or equal to 30% (thirtypercent) compared to vehicle can be especially desired.

The total-cholesterol and triglyceride lowering effects of a Compound ofthis invention is also studied. The data for reduction in totalcholesterol and triglyceride levels after treatment with a compound ofthis invention for 14 days is compared to the vehicle to suggestcompounds that can be particularly desired.

Method to Elucidate the Fibrinogen-Lowering Effect of PPAR•Modulators

Zucker Fatty Rat Model:

The life phase of the study on fibrinogen-lowering effect of compoundsof this invention is part of the life phase procedures for theantidiabetic studies of the same compounds. On the last (14^(th)) day ofthe treatment period, with the animals placed under surgical anesthesia,˜3 ml of blood is collected, by cardiac puncture, into a syringecontaining citrate buffer. The blood sample is chilled and centrifugedat 4° C. to isolate the plasma that is stored at −70° C. prior tofibrinogen assay.

Quantification of Rat Plasma Fibrinogen:

Rat plasma fibrinogen levels are quantified by using a commercial assaysystem consists of a coagulation instrument following the manufacturer'sprotocol. In essence, 100 ul of plasma is sampled from each specimen anda 1/20 dilution is prepared with buffer. The diluted plasma is incubatedat 37° C. for 240 seconds. Fifty microliters of clotting reagentthrombin solution (provided by the instrument's manufacturer in astandard concentration) is then added. The instrument monitores theclotting time, a function of fibrinogen concentration quantified withreference to standard samples.

Results:

Compounds of this invention are capable of lowering fibrinogen level invivo. Compounds that lower fibrinogen level greater than vehicle can beespecially desired.

Cholesterol and triglyceride lowering effects of compounds of thisinvention are also produced in Zucker rats.

Method to Elucidate the Anti-body Weight Gain and Anti-appetite Effectsof Compounds of this Invention

Fourteen-Day Study in Zucker Fatty Rat¹ or ZDF Rat² Models:

Male Zucker Fatty rats, non-diabetic (Charles River Laboratories,Wilmington, Mass.) or male ZDF rats (Genetic Models, Inc, Indianapolis,Ind.) of comparable age and weight are acclimated for 1 week prior totreatment. Rats are on normal chow and water is provided ad libitumthroughout the course of the experiment.

Test compounds are dissolved in an aqueous vehicle such that each ratreceives once a day approximately 1 ml of the solution by garvage atdoses 0.1, 0.3, 1 and 3 mg/kg body weight. Fenofibrate (Sigma Chemical,prepared as a suspension in the same vehicle) a known alpha-agonistgiven at doses of 300 mg/kg, as well as the vehicle are controls. Dosingis performed daily in the early morning for 14 days. Over the course ofthe experiment, body weight and food consumption are monitored.

Using this assay, compounds of this invention are found to result insignificant weight reduction.

EQUIVALENTS

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

1. A compound of the Formula I:

and pharmaceutically acceptable salts thereof, wherein: (a) R3 ishydrogen; (b) R4 is hydrogen; (c) R5 is selected from the groupconsisting of (C₁-C₆) alkyl, (C₁-C₆) alkenyl, aryl(C₀-C₄)alkyl,aryloxy(C₀-C₄)alkyl, arylthio(C₀-C₄)alkyl, wherein saidaryl(C₀-C₄)alkyl, aryloxy(C₀-C₄)alkyl, and arylthio(C₀-C₄)alkyl are eachindependently optionally substituted with from one to three substituentseach independently selected from R5′; (d) R5′ are each independentlyselected from the group consisting of halo, —(O)—(C₁-C₅)alkylCOOH, C₁-C₅alkyl, C₁-C₅ alkylCOOH, and CF₃; (e) R6 is selected from the groupconsisting of, optionally substituted pyridinyl, optionally substitutedpyrimidinyl, and optionally substituted pyrazinyl wherein saidsubstituted pyridinyl, pyrimidinyl, and pyrazinyl are substituted withfrom one to three substituents independently selected from R6′; (f) R6′is independently selected from the group consisting of CF₃, C₁-C₄ alkyl,halo, hydroxy(C₁-C₃)alkyl, C₁-C₃ alkoxy, and —C(O)CH₃; (g) R7 and R8 areeach independently selected from the group consisting of hydrogen,(C₁-C₆) alkyl, and trifluoromethyl; (h) R9 and R10 are eachindependently selected from the group consisting of hydrogen, (C₁-C₄)alkyl, (C₁-C₃) alkenyl, halo, and (C₁-C₄) alkoxy; (i) Q is selected fromthe group consisting of O, C, and a single bond; (j) W is selected fromthe group consisting of O, S, and SO₂; (k) X is C_(m)H_(2m); (l) m isselected from the group consisting of 0, 1 and 2; (m) Y and Z are eachindependently selected from the group consisting of N, S, and O, withthe proviso that at least one of Y and Z is selected from the groupconsisting of S and O; (n) A is COOH; (o) n is 0, 1, 2 or 3; (p) R19 isselected from the group consisting of hydrogen, C1-C4alkyl andarylmethyl, wherein said alky and arylmethyl are each optionallysubstituted with from one to three substituents each independentlyselected from R19′; and (q) R19′ are each independently selected fromthe group consisting of halo, —(O)—(C₁-C₅)alkylCOOH, C₁-C₅ alkyl, andCF₃; with the proviso that when R3 and R4 are each hydrogen, and atleast one selected from the group consisting of R7 and R8 is CF₃, thenR5 is selected from the group consisting of (C₃-C₆) alkyl, (C₁-C₆)alkenyl, substituted aryl(C₀-C₄)alkyl, substituted aryloxy(C₀-C₄)alkyl,substituted arylthio(C₀-C₄)alkyl, unsubstituted aryl(C₀-C₄)alkyl,unsubstituted aryloxy(C₀-C₄)alkyl, and unsubstitutedarylthio(C₀-C₄)alkyl.
 2. A compound as claimed by claim 1 wherein W isO.
 3. A compound as claimed by claim 1 wherein W is S.
 4. A compound asclaimed by claim 1 wherein W is bonded to the phenyl meta in relation toQ.
 5. A compound as claimed by claim 1 wherein R5 is (C₁-C₃)alkyl.
 6. Acompound as claimed by claim 1 wherein R5 is methyl.
 7. A compound asclaimed by claim 1 wherein R5 is an optionally substituted groupselected from aryl(C₀-C₄)alkyl, aryloxy(C₀-C₄)alkyl, andarylthio(C₀-C₄)alkyl.
 8. A compound as claimed by claim 1 wherein R5 isoptionally substituted phenyl-alkyl.
 9. A compound as claimed by claim 1wherein Z is N.
 10. A compound as claimed by claim 1 wherein Y is O. 11.A compound as claimed by claim 1 wherein Y is S.
 12. A pharmaceuticalcomposition, comprising a pharmaceutically acceptable carrier and atleast one compound as claimed by claim
 1. 13. A method of modulating aperoxisome proliferator activated receptor, comprising the step ofcontacting the receptor with at least one compound as claimed byclaim
 1. 14. A method of claim 13 wherein the PPAR modulator is a PPARagonist.
 15. A method of treating diabetes mellitus in a mammal,comprising the step of administering to the mammal in need thereof, atherapeutically effective amount of at least one compound of claim 1.16. A method of treating atherosclerosis in a mammal, comprising thestep of administering to the mammal in need thereof, a therapeuticallyeffective amount of at least one compound of claim
 1. 17. A compound asclaimed by claim 1 wherein the compound is radiolabeled.
 18. A compoundas claimed by claim 1 wherein the compound is selected from the groupconsisting of:3-[4-(2-{2-[6-(2-Fluoro-phenyl)-pyridin-3-yl]-5-methyl-thiazol-4-yl}-ethoxy)-2-methyl-phenyl]-propionicacid,3-[4-(2-{2-[6-(3-Fluoro-phenyl)-pyridin-3-yl]-5-methyl-thiazol-4-yl}-ethoxy)-2-methyl-phenyl]-propionicacid,3-[4-(2-{2-[6-(4-Fluoro-phenyl)-pyridin-3-yl]-5-methyl-thiazol-4-yl}-ethoxy)-2-methyl-phenyl]-propionicacid,3-[4-(2-{2-[6-phenyl-pyridin-3-yl]-5-methyl-thiazol-4-yl}-ethoxy)-2-methyl-phenyl]-propionicacid,3-[4-(2-{2-[6-(2-methyl-phenyl)-pyridin-3-yl]-5-methyl-thiazol-4-yl}-ethoxy)-2-methyl-phenyl]-propionicacid,3-[4-(2-{2-[6-(3-methyl-phenyl)-pyridin-3-yl]-5-methyl-thiazol-4-yl}-ethoxy)-2-methyl-phenyl]-propionicacid,3-[4-(2-{2-[6-(4-methyl-phenyl)-pyridin-3-yl]-5-methyl-thiazol-4-yl}-ethoxy)-2-methyl-phenyl]-propionicacid,3-{4-[2-(2-[2,2′]Bipyridinyl-5-yl-5-methyl-thiazol-4-yl)-ethoxy]-2-methyl-phenyl}-propionicacid,3-(2-Methyl-4-{2-[5-methyl-2-(6-phenoxy-pyridin-3-yl)-thiazol-4-yl]-ethoxy}-phenyl)-propionicacid,3-(2-Methyl-4-{2-[5-methyl-2-(6-phenoxy-pyridin-3-yl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid,3-(2-Methyl-4-{2-[5-methyl-2-(6-phenylsulfanyl-pyridin-3-yl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid,3-(2-Methyl-4-{2-[5-methyl-2-(6-phenyl-pyridin-3-yl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid, 6-chloro-nicotinic acid 3-methoxycarbonyl-1-methyl-2-oxo-propylester,3-[4-(2-{2-[6-(2-Fluoro-phenyl)-pyridin-3-yl]-5-methyl-oxazol-4-yl}-ethoxy)-2-methyl-phenyl]-propionicacid,3-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-2-yl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionicacid,3-(2-Methyl-4-{2-[5-methyl-2-(4-pyrimidin-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid,3-{4-[2-(2-[2,2′]Bipyridinyl-5-yl-5-methyl-oxazol-4-yl)-ethoxy]-2-methyl-phenyl}-propionicacid,3-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid,3-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-4-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid,3-[2-Methyl-4-(2-{5-methyl-2-[4-(5-methyl-pyridin-2-yl)-phenyl]-oxazol-4-yl}-ethoxy)-phenyl]-propionicacid,3-[2-Methyl-4-(2-{5-methyl-2-[4-(6-methyl-pyridin-2-yl)-phenyl]-oxazol-4-yl}-ethoxy)-phenyl]-propionicacid,3-[2-Methyl-4-(2-{5-methyl-2-[4-(3-methyl-pyridin-2-yl)-phenyl]-oxazol-4-yl}-ethoxy)-phenyl]-propionicacid,3-(2-Methyl-4-{2-[5-methyl-2-(4-pyrimidin-4-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid,3-(2-Methyl-4-{3-[5-methyl-2-(4-pyridin-2-yl-phenyl)-oxazol-4-yl]-propoxy}-phenyl)-propionicacid,3-[2-Methyl-4-(2-{5-methyl-2-[3-(5-methyl-pyridin-2-yl)-phenyl]-oxazol-4-yl}-ethoxy)-phenyl]-propionicacid,3-[2-Methyl-4-(2-{5-methyl-2-[3-(6-methyl-pyridin-2-yl)-phenyl]-oxazol-4-yl}-ethoxy)-phenyl]-propionicacid,3-[2-Methyl-4-(2-{5-methyl-2-[3-pyridin-2-yl-phenyl]-oxazol-4-yl}-ethoxy)-phenyl]-propionicacid,3-(2-Methyl-4-{2-[5-methyl-2-(3-pyrimidin-4-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid,3-(2-Methyl-4-{2-[5-methyl-2-(3-pyrimidin-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid,3-(2-Methyl-4-{2-[5-methyl-2-(4-pyrimidin-2-yl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionicacid,3-(2-Methyl-4-{2-[5-methyl-2-(4-pyrazin-2-yl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionicacid,3-(2-Methyl-4-{2-[5-methyl-2-(4-pyrazin-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid,3-(2-Methyl-4-{2-[5-methyl-2-(3-pyrazin-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid,3-[2-Methyl-4-(2-{5-methyl-2-[4-(6-methyl-pyridazin-3-yl)-phenyl]-oxazol-4-yl}-ethoxy)-phenyl]-propionicacid,3-(2-Methyl-4-{2-[5-methyl-2-(3-pyrazin-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid,3-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-3-yl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionicacid,3-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-4-yl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionicacid,3-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-3-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid,3-(2-Methyl-4-{2-[5-methyl-2-(3-pyridin-3-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid, and3-(2-Methyl-4-{2-[5-methyl-2-(3-pyridin-4-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionicacid.
 19. A compound selected from the group consisting of:(3-{2-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-aceticacid,(3-{2-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-aceticacid,(3-{2-[5-Propyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-aceticacid,(4-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-aceticacid,(3-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-phenyl)-aceticacid,{3-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-ylmethoxy]-phenyl}-aceticacid,{3-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-ylmethylsulfanyl]-phenyl}-aceticacid,(3-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethylsulfanyl}-phenyl)-aceticacid,{3-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-aceticacid,{4-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-2-propyl-phenoxy}-aceticacid,3-{4-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methyl-phenyl}-propionicacid,3-{4-[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methyl-phenyl}-propionicacid,3-{4-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-2-methyl-phenyl}-propionicacid,3-{2-Methyl-4-[4-propyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-phenyl}-propionicacid,3-{2-Methyl-4-[4-phenethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-phenyl}-propionicacid,3-{2-Methyl-4-[4-phenethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-propionicacid,3-{2-Methyl-4-[4-propyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-propionicacid,3-{4-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methyl-phenyl}-propionicacid,3-{4-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-2-methyl-phenyl}-propionicacid,3-{4-[4-[2-(2-Chloro-6-fluoro-phenyl)-ethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methyl-phenyl}-propionicacid,3-{2-Methyl-4-[4-phenylsulfanylmethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-propionicacid,3-{4-[4-(2-Chloro-6-fluoro-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methyl-phenyl}-propionicacid,3-{2-Methyl-4-[4-phenoxymethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-propionicacid,3-{4-[4-(3,5-Bis-trifluoromethyl-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methyl-phenyl}-propionicacid,3-{4-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methoxy-phenyl}-propionicacid,3-{4-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-propionicacid,3-{2-Methyl-4-[4-phenoxymethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-phenyl}-propionicacid,3-{4-[4-[2-(2-Chloro-6-fluoro-phenyl)-ethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-2-methyl-phenyl}-propionicacid,3-{2-Methyl-4-[4-phenoxymethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-phenyl}-propionicacid,3-{2-Methyl-4-[4-phenylsulfanylmethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-phenyl}-propionicacid,3-(2-Methyl-4-{2-[5-propyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionicacid,3-(2-Methyl-4-{2-[5-propyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethylsulfanyl}-phenyl)-propionicacid,3-{4-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-ylmethoxy]-2-methyl-phenyl}-propionicacid,3-(2-Methyl-4-{[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethyl]-carbamoyl}-phenyl)-propionicacid,3-(4-{[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-amino}-2-methyl-phenyl)-propionicacid,3-(4-{2-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-acetylamino}-2-methyl-phenyl)-propionicacid,3-[4-({[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-methyl-amino}-methyl)-2-methyl-phenyl]-propionicacid,3-[4-({[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-amino}-methyl)-2-methyl-phenyl]-propionicacid,3-(2-Methyl-4-{[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-phenyl)-propionicacid,3-[4-({Bis-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-methyl)-2-methyl-phenyl]-propionicacid TFA salt,3-[2-Methyl-4-({methyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-methyl)-phenyl]-propionicacid methyl ester TFA salt,3-(4-{Methoxycarbonyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-2-methyl-phenyl)-propionicacid,3-{2-Methyl-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxymethyl]-phenyl}-propionicacid,3-{4-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxymethyl]-2-methyl-phenyl}-propionicacid, and{3-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-aceticacid.
 20. A compound as claimed by claim 1 wherein Q is C.
 21. Acompound as claimed by claim 1 wherein Q is O.
 22. A compound as claimedby claim 1 wherein Q is a bond.